Skip to main content

Advertisement

SpringerLink
Log in

Roles of Ki-67 and p16 as biomarkers for unknown primary head and neck squamous cell carcinoma

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

Abstract

Purpose

Treatment guidelines have not been established for unknown primary head and neck squamous cell carcinoma (SCC). For these patients, chemoradiotherapy (CRT) can provide a better prognosis than that for patients with other head and neck cancers. The presence of HPV in the tumor is associated with a better outcome. However, not all patients with HPV-positive unknown primary head and neck SCC experience good treatment outcomes in actual clinical settings.

Methods

We thus retrospectively determined the Ki-67 proliferation index and p16 expression status to assess the associations of these parameters with treatment outcomes of patients with unknown primary head and neck SCC.

Results

The subjects were 13 patients who underwent CRT after surgery or excision biopsy between 1999 and 2016. The 2- and 5-year overall survival (OS) rate was 76.9% and 68.4%, respectively. The prognostic factor was age. There was no significant difference in survival between patients with a high Ki-67 vs. low Ki-67 or between patients with p16-positive vs. p16-negative metastases OS. However, all p16-positive patients with low Ki-67 showed good locoregional control.

Conclusions

The combination of ki67 expression and p16 expression status may allow prediction of local control more accurately than p16 expression status alone.

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

References

  1. Demiroz C, Vainshtein JM, Koukourakis GV et al (2014) Head and neck squamous cell carcinoma of unknown primary: neck dissection and radiotherapy or definitive radiotherapy. Head Neck 36:1589–1595. https://doi.org/10.1002/hed.23479

    Article  PubMed  Google Scholar 

  2. Mirghani H, Amen F, Tao Y et al (2015) Increased radiosensitivity of HPV-positive head and neck cancers: molecular basis and therapeutic perspectives. Cancer Treat Rev 41:844–852. https://doi.org/10.1016/j.ctrv.2015.10.001

    Article  CAS  PubMed  Google Scholar 

  3. Fakhry C, Westra WH, Li S et al (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100:261–269. https://doi.org/10.1093/jnci/djn011

    Article  CAS  PubMed  Google Scholar 

  4. Kofler B, Laban S, Busch CJ et al (2014) New treatment strategies for HPV-positive head and neck cancer. Eur Arch Otorhinolaryngol 271:1861–1867. https://doi.org/10.1007/s00405-013-2603-0

    Article  CAS  PubMed  Google Scholar 

  5. Kimple RJ, Harari PM (2014) Is radiation dose reduction the right answer for HPV-positive head and neck cancer? Oral Oncol 50:560–564. https://doi.org/10.3978/j.issn.2305-5839.2015.01.37

    Article  CAS  PubMed  Google Scholar 

  6. Patel RS, Clark J, Wyten R et al (2007) Squamous cell carcinoma from an unknown head and neck primary site: a “selective treatment” approach. Arch Otolaryngol Head Neck Surg 133:1282–1287

    Article  PubMed  Google Scholar 

  7. Cerezo L, Raboso E, Ballesteros AI (2011) Unknown primry cancer of the head and neck:a multidisciplinary approach. Clin Transl Oncol 13:88–97. https://doi.org/10.1007/s12094-011-0624-y

    Article  PubMed  Google Scholar 

  8. Boscolo-Rizzo P, Gava A et al (2007) Carcinoma metastatic to cervical lymph nodes from an occult primary tumor: the outcome after combined-modality therapy. Ann Surg Oncol 14:1575–1582

    Article  PubMed  Google Scholar 

  9. Strojan P, Ferlito A, Lanqendijk JA et al (2013) Contemporary management of lymph node metastases from an unknown primary to the neck:II. a review of therapeutic options. Head Neck 35:286–293. https://doi.org/10.1002/hed.21899

    Article  PubMed  Google Scholar 

  10. Werner JA, Dünne AA (2001) Value of neck dissection in patients with squamous cell carcinoma of unknown primary. Onkologie 24:16–20

    CAS  PubMed  Google Scholar 

  11. Grau C, Johansen LV, Jakobsen J et al (2000) Cervical lymph node metastases from unknown primary tumors. Results from a national survey by the Danish Society for Head and Neck Oncology. Radiother Oncol 55:121–129

    Article  CAS  PubMed  Google Scholar 

  12. Argiris A, Smith SM, Stenson K et al (2003) Concurrent chemoradiotherapy for N2 or N3 squamous cell carcinoma of the head and neck from an occult primary. Ann Oncol 14:1306–1311

    Article  CAS  PubMed  Google Scholar 

  13. Nieder C, Ang KK (2002) Cervical lymph node metastases from occult squamous cell carcinoma. Curr Treat Options Oncol 3:33–40

    Article  PubMed  Google Scholar 

  14. Ligey A, Gentil J, Créhange G et al (2009) Impact of target volumes and radiation technique on loco-regional control and survival for patients with unilateral cervical lymph node metastases from an unknown primary. Radiother Oncol 93:483–487. https://doi.org/10.1016/j.radonc.2009.08.027

    Article  CAS  PubMed  Google Scholar 

  15. Chen AM, Meshman J, Hsu S et al (2018) Oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma involving the cervical lymph nodes of unknown primary origin. Head Neck 40:227–232. https://doi.org/10.1002/hed.24906

    Article  PubMed  Google Scholar 

  16. Dixon PR, Au M, Hosni A et al (2016) Impact of p16 expression, nodal status, and smoking on oncologic outcomes of patients with head and neck unknown primary squamous cell carcinoma. Head Neck 38:1347–1353. https://doi.org/10.1002/hed.24441

    Article  PubMed  Google Scholar 

  17. Straetmans J, Vent J, Lacko M et al (2015) Management of neck metastases of unknown primary origin united in two European centers. Eur Arch Otorhinolaryngol 272:195–205

    Article  PubMed  Google Scholar 

  18. Szentkuti G, Danos K, Brauswetter D et al (2015) Correlations between prognosis and regional biomarker profiles in head and neck squamous cell carcinomas. Pathol Oncol Res 21:643–650. https://doi.org/10.1007/s12253-014-9869-4

    Article  CAS  PubMed  Google Scholar 

  19. Gioacchini FM, Alicandri-Ciufelli M, Magliulo G et al (2015) The clinical relevance of Ki-67 expression in laryngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol 272:1569–1576. https://doi.org/10.1007/s00405-014-3117-0

    Article  PubMed  Google Scholar 

  20. National Cancer Institute Common terminology criteria for adverse events v4.0 (CTCAE) (2016) http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcae_4_with_lay_terms.pdf. Accessed 12 November 2017

  21. RTOG 1016 Protocol Information (2016) Phase III Trial of Radiotherapy Plus Cetuximab Versus Chemoradiotherapy in HPV-Associated Oropharynx Cancer Radiation Therapy Oncology Group. https://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=1016. Accessed 11 May 2018

  22. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML (2012) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363:24–35. https://doi.org/10.1056/NEJMoa0912217

    Article  CAS  Google Scholar 

  23. Park GC, Lee M, Roh JL et al (2012) Human papillomavirus and p16 detection in cervical lymph node metastases from an unknown primary tumor. Oral Oncol 48:1250–1256. https://doi.org/10.1016/j.oraloncology.2012.05.026

    Article  CAS  PubMed  Google Scholar 

  24. Cuaron J, Rao S, Wolden S, Zelefsky M et al (2016) Patterns of failure in patients with head and neck carcinoma of unknown primary treated with radiation therapy. Head Neck 38:E426–E431. https://doi.org/10.1002/hed.24013

    Article  PubMed  Google Scholar 

  25. Prigge ES, Toth C, Dyckhoff G et al (2015) p16(INK4a) /Ki-67 co-expression specifically identifies transformed cells in the head and neck region. Int J Cancer 136:1589–1599. https://doi.org/10.1002/ijc.29130

    Article  CAS  PubMed  Google Scholar 

  26. Linxweiler M, Bochen F, Wemmert S et al (2015) Combination of p16(INK4a)/Ki67 immunocytology and HPV polymerase chain reaction for the noninvasive analysis of HPV involvement in head and neck cancer. Cancer Cytopathol 123:219–229. https://doi.org/10.1002/cncy.21512

    Article  CAS  PubMed  Google Scholar 

  27. Ciesielska U, Zatonski T, Nowinska K et al (2017) Expression of cell cycle-related proteins p16, p27 and Ki-67 proliferating marker in laryngeal squamous cell carcinomas and in laryngeal papillomas. Anticancer Res 37:2407–2415

    Article  CAS  PubMed  Google Scholar 

  28. Liu J, Zhang M, Rose B et al (2015) Ki67 expression has prognostic significance in relation to human papillomavirus status in oropharyngeal squamous cell carcinoma. Ann Surg Oncol 22:1893–1900. https://doi.org/10.1245/s10434-014-4237-x

    Article  PubMed  Google Scholar 

  29. Rittà M, De Andrea M, Mondini M et al (2009) Cell cycle and viral and immunologic profiles of head and neck squamous cell carcinoma as predictable variables of tumor progression. Head Neck 31:318–327. https://doi.org/10.1002/hed.20977

    Article  PubMed  Google Scholar 

  30. Machtay M, Moughan J, Trotti A et al (2008) Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol 26:3582–3589. https://doi.org/10.1200/JCO.2007.14.8841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Givens DJ, Karnell LH, Gupta AK et al (2009) Adverse events associated with concurrent chemoradiation therapy in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 135:1209–1217. https://doi.org/10.1001/archoto.2009.174

    Article  PubMed  Google Scholar 

  32. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidlines®) Senior adult oncology Version 2.2014. © 2014 National Comprehensive Cancer Network, Inc. NCCN.org. Accessed 1 Nov 2018

  33. Lewis JS Jr, Thorstad WL, Chernock RD et al (2010) p16 positive oropharyngeal squamous cell carcinoma:an entity with a favorable prognosis regardless of tumor HPV status. Am J Surg Pathol 34:1088–1096. https://doi.org/10.1097/PAS.0b013e3181e84652

    Article  PubMed  Google Scholar 

  34. Smeets SJ, Hesselink AT, Speel EJ et al (2007) A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer 21:2465–2472

    Article  CAS  Google Scholar 

  35. Chernock RD, El-Mofty SK, Thorstad WL et al (2009) HPV-related nonkeratinizing squamous cell carcinoma of the oropharynx: utility of microscopic features in predicting patient outcome. Head Neck Pathol 3:186–194. https://doi.org/10.1007/s12105-009-0126-1

    Article  PubMed  PubMed Central  Google Scholar 

  36. Penault-Llorca F, André F, Sagan C, Lacroix-Triki M et al (2009) Ki67 expression and docetaxel efficacy in patients with estrogen receptor-positive breast cancer. J Clin Oncol 27:2809–2815. https://doi.org/10.1200/JCO.2008.18.2808

    Article  CAS  PubMed  Google Scholar 

  37. Gillison ML, D’Souza G, Westra W et al (2008) Distinct risk factor profiles for human papillomavirus type 16-positive and Human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 100:407–420. https://doi.org/10.1093/jnci/djn025

    Article  PubMed  Google Scholar 

  38. Fallai C, Perrone F, Licitra L et al (2009) Oropharygeal squamous cell carcinoma treated with radiotherapy or radiochemotherapy: prognostic role of P53 and HPV status. Int J Radiat Oncol Biol Phys 75:1053–1059. https://doi.org/10.1016/j.ijrobp.2008.12.088

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Bierta Barfod for her contribution to the language editing of this manuscript.

Funding

No specific funding was received for this research.

Author information

Authors and Affiliations

  1. Department of Radiology, Nihon University School of Medicine, 30-1 Oyaguchi Kami-cho, Itabashi-ku, 173-8610, Tokyo, Japan

    Toshiya Maebayashi, Naoya Ishibashi, Takuya Aizawa & Masakuni Sakaguchi

  2. Radiology Clinic, Sonoda Medical Hospital, Adachi-ku, 121-0064, Tokyo, Japan

    Tsutomu Saito

  3. Department of Radiation Oncology, St. Luke’s International Hospital, Chuo-ku, 104-8560, Tokyo, Japan

    Jiro Kawamori

  4. Department of Radiation Oncology, Kawasaki Saiwai Hospital, 212-0041, Kawasaki, Kanagawa, Japan

    Yoshiaki Tanaka

  5. Department of Human Pathology, Division of Pathology and Microbiology, Nihon University School of Medicine, Itabashi-ku, 173-8610, Tokyo, Japan

    Yukari Hirotani & Taku Homma

Authors
  1. Toshiya Maebayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naoya Ishibashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takuya Aizawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masakuni Sakaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tsutomu Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jiro Kawamori
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshiaki Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yukari Hirotani
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Taku Homma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshiya Maebayashi.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Ethical approval retrospective studies

This study was approved by the institutional review board, and patient informed consent was obtained. (Trial registration number: Nihon University Itabashi Hospital Clinical Research Center RK-170214-9).

Informed consent

Informed consent was obtained from all individual participants included in the study. Additional informed consent was obtained from all individual participants for whom identifying information is included in this article. Documentation of informed consent for treatment was signed by each patient and placed in the patient’s medical record.

Research data policy

The dataset supporting the conclusions of this article is included within the article.

Consent for publication

copy of the written consent is available for review by the Editor-in-Chief of this journal.

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

Maebayashi, T., Ishibashi, N., Aizawa, T. et al. Roles of Ki-67 and p16 as biomarkers for unknown primary head and neck squamous cell carcinoma. Eur Arch Otorhinolaryngol 276, 1221–1229 (2019). https://doi.org/10.1007/s00405-019-05338-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00405-019-05338-3

Keywords

Search

Navigation