Skip to main content
SpringerLink
Log in

Cytokeratin 7 and 19 expression in oropharyngeal and oral squamous cell carcinoma

  • Head and Neck
  • Published:
European Archives of Oto-Rhino-Laryngology Aims and scope Submit manuscript

Abstract

Purpose

The precise etiopathogenesis of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), and reasons for predilection for crypt epithelium, remain uncertain. The purpose of this study is to investigate the interaction between HPV and specific cytokeratins 7 (CK7) and 19 (CK19) in crypt epithelium.

Methods

This is a retrospective cohort study of patients presenting between 1999 and 2015 at a tertiary referral center. CK7 and CK19 positivity and H Scores were determined by immunohistochemistry. Disease-specific and overall survival rates were analyzed.

Results

There were 253 patients presenting with OPSCC (134), squamous cell carcinoma (SCC) of unknown primary site (22), and oral tongue SCC (97). Primary tumor CK7 and CK19 positivity and H Scores were significantly higher in HPV-positive OPSCC than HPV-negative OPSCC and oral tongue SCC. Higher CK19 Scores, but not CK7 Scores, were also seen in regional metastases from HPV-positive OPSCC than other sites. No impact on disease-specific or overall survival was identified on multivariate analysis.

Conclusion

The increased expression of CK7 and CK19 in HPV-positive OPSCC compared to HPV-negative disease supports the theory for a role for these cytokeratins in the etiopathogenesis of HPV-related OPSCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Availability of data and material

Available from corresponding author.

References

  1. Sharma SJ, Wagner S, Reder HSF, Kroll T, Wuerdemann N, Klussmann JP, Wittekindt C (2018) The 8th edition AJCC/UICC TNM staging for p16-positive oropharyngeal carcinoma: is there space for improvement? Eur Arch Otorhinolaryngol 275(12):3087–3091. https://doi.org/10.1007/s00405-018-5156-4

    Article  PubMed  Google Scholar 

  2. Roberts S, Evans D, Mehanna H, Parish JL (2019) Modelling human papillomavirus biology in oropharyngeal keratinocytes. Philos Trans R Soc B 374(1773):20180289. https://doi.org/10.1098/rstb.2018.0289

    Article  CAS  Google Scholar 

  3. Begum S, Cao D, Gillison M, Zahurak M, Westra WH (2005) Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. Clin Cancer Res 11(16):5694–5699. https://doi.org/10.1158/1078-0432.CCR-05-0587

    Article  CAS  PubMed  Google Scholar 

  4. Kim SH, Koo BS, Kang S, Park K, Kim H, Lee KR, Lee MJ, Kim JM, Choi EC, Cho NH (2007) HPV integration begins in the tonsillar crypt and leads to the alteration of p16, EGFR and c-myc during tumor formation. Int J Cancer 120(7):1418–1425. https://doi.org/10.1002/ijc.22464

    Article  CAS  PubMed  Google Scholar 

  5. Thavaraj S, Stokes A, Mazuno K, Henley-Smith R, Suh YE, Paleri V, Tavassoli M, Odell E, Robinson M (2014) Patients with HPV-related tonsil squamous cell carcinoma rarely harbour oncogenic HPV infection at other pharyngeal sites. Oral Oncol. https://doi.org/10.1016/j.oraloncology.2013.12.012

    Article  PubMed  Google Scholar 

  6. Pai SI, Westra WH (2009) Molecular pathology of head and neck cancer: implications for diagnosis, prognosis, and treatment. Annu Rev Pathol 4:49–70. https://doi.org/10.1146/annurev.pathol.4.110807.092158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rautava J, Syrjanen S (2012) Biology of human papillomavirus infections in head and neck carcinogenesis. Head Neck Pathol 6(Suppl 1):S3-15. https://doi.org/10.1007/s12105-012-0367-2

    Article  PubMed  Google Scholar 

  8. Fujimura Y, Takeda M, Ikai H, Haruma K, Akisada T, Harada T, Sakai T, Ohuchi M (2004) The role of M cells of human nasopharyngeal lymphoid tissue in influenza virus sampling. Virchows Arch 444(1):36–42. https://doi.org/10.1007/s00428-003-0898-8

    Article  PubMed  Google Scholar 

  9. Moutsopoulos NM, Vazquez N, Greenwell-Wild T, Ecevit I, Horn J, Orenstein J, Wahl SM (2006) Regulation of the tonsil cytokine milieu favors HIV susceptibility. J Leukoc Biol 80(5):1145–1155. https://doi.org/10.1189/jlb.0306142

    Article  CAS  PubMed  Google Scholar 

  10. Hafkamp HC, Speel EJ, Haesevoets A, Bot FJ, Dinjens WN, Ramaekers FC, Hopman AH, Manni JJ (2003) A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5–8. Int J Cancer 107(3):394–400. https://doi.org/10.1002/ijc.11389

    Article  CAS  PubMed  Google Scholar 

  11. Lace MJ, Anson JR, Klingelhutz AJ, Lee JH, Bossler AD, Haugen TH, Turek LP (2009) Human papillomavirus (HPV) type 18 induces extended growth in primary human cervical, tonsillar, or foreskin keratinocytes more effectively than other high-risk mucosal HPVs. J Virol 83(22):11784–11794. https://doi.org/10.1128/JVI.01370-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Woods RS, Keegan H, White C, Tewari P, O’Regan EM, Toner M, Kennedy S, Martin CM, Timon CV, O’Leary JJ (2017) Cytokeratin 7 in oropharyngeal squamous cell carcinoma: a junctional biomarker for human papillomavirus-related tumours. Cancer Epidemiol Biomark Prevent. https://doi.org/10.1158/1055-9965.EPI-16-0619

    Article  Google Scholar 

  13. Lindberg K, Rheinwald JG (1989) Suprabasal 40 kd keratin (K19) expression as an immunohistologic marker of premalignancy in oral epithelium. Am J Pathol 134(1):89–98

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Chu PG, Weiss LM (2002) Keratin expression in human tissues and neoplasms. Histopathology 40(5):403–439. https://doi.org/10.1046/j.1365-2559.2002.01387.x

    Article  CAS  PubMed  Google Scholar 

  15. Depondt J, Shabana AH, Sawaf H, Gehanno P, Forest N (1999) Cytokeratin alterations as diagnostic and prognostic markers of oral and pharyngeal carcinomas. A prospective study. Eur J Oral Sci 107(6):442–454. https://doi.org/10.1046/j.0909-8836.1999.eos107605.x

    Article  CAS  PubMed  Google Scholar 

  16. Favia G, Kanduc D, Lo Muzio L, Lucchese A, Serpico R (2004) Possible association between HPV16 E7 protein level and cytokeratin 19. Int J Cancer 111(5):795–797. https://doi.org/10.1002/ijc.20343

    Article  CAS  PubMed  Google Scholar 

  17. Santoro A, Pannone G, Ninivaggi R, Petruzzi M, Santarelli A, Russo GM, Lepore S, Pietrafesa M, Laurenzana I, Leonardi R, Bucci P, Natalicchio MI, Lucchese A, Papagerakis S, Bufo P (2015) Relationship between CK19 expression, deregulation of normal keratinocyte differentiation pattern and high risk-human papilloma virus infection in oral and oropharyngeal squamous cell carcinoma. Infectious agents and cancer 10:46. https://doi.org/10.1186/s13027-015-0041-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kanduc D (2002) Translational regulation of human papillomavirus type 16 E7 mRNA by the peptide SEQIKA, shared by rabbit alpha(1)-globin and human cytokeratin 7. J Virol 76(14):7040–7048

    Article  CAS  Google Scholar 

  19. Lee H, Lee H, Cho YK (2017) Cytokeratin7 and cytokeratin19 expression in high grade cervical intraepithelial neoplasm and squamous cell carcinoma and their possible association in cervical carcinogenesis. Diagn Pathol 12(1):18. https://doi.org/10.1186/s13000-017-0609-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Park JM, Jung CK, Choi YJ, Lee KY, Kang JH, Kim MS, Hu HJ (2010) The use of an immunohistochemical diagnostic panel to determine the primary site of cervical lymph node metastases of occult squamous cell carcinoma. Hum Pathol 41(3):431–437. https://doi.org/10.1016/j.humpath.2009.09.001

    Article  PubMed  Google Scholar 

  21. Babiker AY, Rahmani AH, Abdalaziz MS, Albutti A, Aly SM, Ahmed HG (2014) Expressional analysis of p16 and cytokeratin19 protein in the genesis of oral squamous cell carcinoma patients. Int J Clin Exp Med 7(6):1524–1530

    PubMed  PubMed Central  Google Scholar 

  22. Molony P, Kharytaniuk N, Boyle S, Woods RSR, O’Leary G, Werner R, Heffron C, Feeley L, Sheahan P (2017) Impact of positive margins on outcomes of oropharyngeal squamous cell carcinoma according to p16 status. Head Neck 39(8):1680–1688. https://doi.org/10.1002/hed.24824

    Article  PubMed  Google Scholar 

  23. Molony P, Werner R, Martin C, Callanan D, Sheahan P, Heffron C, Feeley L (2019) Tumour cell anaplasia and multinucleation as prognosticators in oropharyngeal squamous cell carcinoma. Head Neck Pathol. https://doi.org/10.1007/s12105-019-01081-7

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jordan RC, Lingen MW, Perez-Ordonez B, He X, Pickard R, Koluder M, Jiang B, Wakely P, Xiao W, Gillison ML (2012) Validation of methods for oropharyngeal cancer HPV status determination in US cooperative group trials. Am J Surg Pathol 36(7):945–954. https://doi.org/10.1097/PAS.0b013e318253a2d1

    Article  PubMed  PubMed Central  Google Scholar 

  25. Mehrad M, Dupont WD, Plummer WD Jr, Lewis JS Jr (2018) Expression and Significance of Cytokeratin 7, a Squamocolumnar Junction Marker, in Head and Neck Squamous Cell Carcinoma. Head Neck Pathol 12(4):448–454. https://doi.org/10.1007/s12105-017-0874-2

    Article  PubMed  Google Scholar 

  26. Chatterjee S, Do Kang S, Alam S, Salzberg AC, Milici J, van der Burg SH, Freeman W, Meyers C (2019) Tissue-specific gene expression during productive human papillomavirus 16 infection of cervical, foreskin, and tonsil epithelium. J Virol. https://doi.org/10.1128/JVI.00915-19

    Article  PubMed  PubMed Central  Google Scholar 

  27. Cho YK, Lee SJ, Woo JJ, Lee H, Lee H (2018) Cytokeratin7 expression in histologic and cytologic specimens of cystic neck metastasis from HPV positive squamous cell carcinoma of the tonsil: a case report. Diagn Cytopathol 46(4):331–335. https://doi.org/10.1002/dc.23841

    Article  PubMed  Google Scholar 

Download references

Funding

Partial financial support was received from the Head and Neck Oncology Fund, South Infirmary Victoria University Hospital.

Author information

Authors and Affiliations

  1. Department of Otolaryngology, South Infirmary Victoria University Hospital, Cork, T12 X23H, Ireland

    Robbie S. R. Woods, Deirdre Callanan & Patrick Sheahan

  2. Department of Histopathology, Cork University Hospital, Cork, Ireland

    Hadeel Jawad, Peter Molony, Reiltin Werner, Cynthia Heffron & Linda Feeley

  3. Department of Surgery, University College Cork, Cork, Ireland

    Patrick Sheahan

  4. ENTO Research Unit, College of Medicine and Health, University College Cork, Cork, Ireland

    Deirdre Callanan, Linda Feeley & Patrick Sheahan

Authors
  1. Robbie S. R. Woods
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Deirdre Callanan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hadeel Jawad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Peter Molony
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Reiltin Werner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cynthia Heffron
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Linda Feeley
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Patrick Sheahan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation and data collection were performed by Robbie Woods, Deirdre Callanan, Hadeel Jawad, Peter Molony and Patrick Sheahan. Data analysis was performed by Robbie Woods, Reiltin Werner, Cynthia Heffron, Linda Feeley and Patrick Sheahan. The first draft of the manuscript was written by Robbie Woods and Patrick Sheahan. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Robbie S. R. Woods.

Ethics declarations

Conflicts of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethics approval

Approval for the study was obtained from the Cork Clinical Research Ethics Committee and the study was performed in accordance with the Ethical Standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Woods, R.S.R., Callanan, D., Jawad, H. et al. Cytokeratin 7 and 19 expression in oropharyngeal and oral squamous cell carcinoma. Eur Arch Otorhinolaryngol 279, 1435–1443 (2022). https://doi.org/10.1007/s00405-021-06894-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00405-021-06894-3

Keywords

Search

Navigation