Skip to main content

Advertisement

SpringerLink
Log in

Introducing Cytology-Based Theranostics in Oral Squamous Cell Carcinoma: A Pilot Program

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

We aimed to evaluate the feasibility and reliability of brush cytology in the biomarker expression profiling of oral squamous cell carcinomas within the concept of theranostics, and to correlate this biomarker profile with patient measurable outcomes. Markers representative of prognostic gene expression changes in oral squamous cell carcinoma was selected. These markers were also selected to involve pathways for which commercially available or investigational agents exist for clinical application. A set of 7 markers were analysed by immunocytochemistry on the archival primary tumour material of 99 oral squamous cell carcinoma patients. We confirmed the feasibility of the technique for the expression profiling of oral squamous cell carcinomas. Furthermore, our results affirm the prognostic significance of the epidermal growth factor receptor (EGFR) family and the angiogenic pathway in oral squamous cell carcinoma, confirming their interest for targeted therapy. Brush cytology appears feasible and applicable for the expression profiling of oral squamous cell carcinoma within the concept of theranostics, according to sample availability.

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

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E (2011) Global cancer statistics, 2008. CA Cancer J Clin 61:69–90

    Article  PubMed  Google Scholar 

  2. Siegel R, Naishadham N, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62:10–29

    Article  PubMed  Google Scholar 

  3. Funkhouser J (2002) Reinventing pharma: the theranostic revolution. Current Drugs Discov 2:17–19

    Google Scholar 

  4. Yu YH, Kuo HK, Chang KW (2008) The evolving transcriptome of head and neck squamous cell carcinoma: a systematic review. PLoS One 3:e3215

    Article  PubMed  PubMed Central  Google Scholar 

  5. Oliveira LR, Ribeiro-Silva A (2011) Prognostic significance of immunohistochemical biomarkers in oral squamous cell carcinoma. Int J Oral Maxillofac Surg 40:298–307

    Article  CAS  PubMed  Google Scholar 

  6. Smith BD, Smith GL, Carter D, Sasaki CT, Haffty BG (2000) Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma. J Clin Oncol 18:2046–2052

    CAS  PubMed  Google Scholar 

  7. Uehara M, Sano K, Ikeda H, Sekine J, Irie A, Yokota T, Tobita T, Ohba S, Inokuchi T (2004) Expression of vascular endothelial growth factor and prognosis of oral squamous cell carcinoma. Oral Oncol 40:321–325

    Article  CAS  PubMed  Google Scholar 

  8. Kyzas PA, Cunha IW, Ioannidis JP (2005) Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis. Clin Cancer Res 11:1434–1440

    Article  CAS  PubMed  Google Scholar 

  9. Shao Z, Zhang WF, Chen XM, Shang ZJ (2008) Expression of EphA2 and VEGF in squamous cell carcinoma of the tongue: correlation with the angiogenesis and clinical outcome. Oral Oncol 44:1110–1117

    Article  CAS  PubMed  Google Scholar 

  10. Argiris A, Kotsakis AP, Hoang T, Worden FP, Savvides P, Gibson MK, Gyanchandani R, Blumenschein Jr GR, Chen HX, Grandis JR, Harari PM, Kies MS, Kim S (2013) Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck. Ann Oncol 24:220–225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Redman MW, Crowley JJ, Herbst RS, Hirsch FR, Gandara DR (2012) Design of a phase III clinical trial with prospective biomarker validation: SWOG S0819. Clin Cancer Res 18:4004–4012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cohen EE, Davis DW, Karrison TG, Seiwert TY, Wong SJ, Nattam S, Kozloff MF, Clark JI, Yan DH, Liu W, Pierce C, Dancey JE, Stenson K, Blair E, Dekker A, Vokes EE (2009) Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet Oncol 10:204–205

    Article  Google Scholar 

  13. Argiris A, Karamouzis MV, Gooding WE, Branstetter BF, Zhong S, Raez LE, Savvides P, Romkes M (2011) Phase II trial of pemetrexed and bevacizumab in patients with recurrent or metastatic head and neck cancer. J Clin Oncol 29:1140–1145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nagatsuka H, Hibi K, Gunduz M, Tsujigiwa H, Tamamura R, Sugahara T, Sasaki A, Nagai N (2005) Various immunostaining patterns of CD31, CD34 and endoglin and their relationship with lymph node metastasis in oral squamous cell carcinomas. J Oral Pathol Med 34:70–76

    Article  PubMed  Google Scholar 

  15. Fujieda S, Sunaga H, Tsuzuki H, Sugimoto C, Tanaka N, Saito H (1998) Expression of platelet-derived endothelial cell growth factor in oral and oropharyngeal carcinoma. Clin Cancer Res 4:1583–1590

    CAS  PubMed  Google Scholar 

  16. Barth PJ, Schweinsberg TS, Ramaswamy A, Moll R (2004) CD34+ fibrocytes, α-smooth muscle antigen-positive myofibroblasts, and CD117 expression in the stroma of invasive squamous cell carcinomas of the oral cavity, pharynx, and larynx. Virchows Arch 444:231–234

    Article  CAS  PubMed  Google Scholar 

  17. Kademani D, Lewis JT, Lamb DH, Rallis DJ, Harrington JR (2009) Angiogenesis and CD34 expression as a predictor of recurrence in oral squamous cell carcinoma. J Oral Maxillofac Surg 67:1800–1805

    Article  PubMed  Google Scholar 

  18. Ascani G, Balercia P, Messi M, Lupi L, Goteri G, Filosa A, Stramazzotti D, Pieramici T, Rubini C (2005) Angiogenesis in oral squamous cell carcinoma. Acta Otorhinolaryngol Ital 25:13–17

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Alcalde RE, Terakado N, Otsuki K, Matsumura T (1997) Angiogenesis and expression of platelet-derived endothelial cell growth factor in oral squamous cell carcinoma. Oncology 54:324–328

    Article  CAS  PubMed  Google Scholar 

  20. Xia W, Lau YK, Zhang HZ, Liu AR, Li L, Kiyokawa N, Clayman GL, Katz RL, Hung MC (1997) Strong correlation between c-erb-2 overexpression and overall patients with oral squamous cell carcinoma. Clin Cancer Res 3:3–9

    CAS  PubMed  Google Scholar 

  21. Xia W, Lau YK, Zhang HZ, Xiao FY, Johnston DA, Liu AR, Li L, Katz RL, Hung MC (1999) Combination of EGFR, HER- 2/neu and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members. Clin Cancer Res 5:4164–4174

    CAS  PubMed  Google Scholar 

  22. Ang KK, Berkey BA, Tu X, Zhang HZ, Katz R, Hammond EH, Fu KK, Milas L (2002) Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 62:7350–7356

    CAS  PubMed  Google Scholar 

  23. Kong A, Leboucher P, Leek R, Calleja V, Winter S, Harris A, Parker PJ, Larijani B (2006) Prognostic value of an activation state marker for epidermal growth factor receptor in tissue microarrays of head and neck cancer. Cancer Res 66:2834–2843

    Article  CAS  PubMed  Google Scholar 

  24. Albuquerque Jr RL, Miguel MC, Costa AL, Souza LB (2003) Correlation of c-erbB-2 and S-100 expression with the malignancy grading and anatomical site in oral squamous cell carcinoma. Int J Exp Pathol 84:259–265

    Article  PubMed  Google Scholar 

  25. Ulanovski D, Stern Y, Roizman P, Shpitzer T, Popovtzer A, Feinmesser R (2004) Expression of EGFR and cerb-B2 as prognostic factors in cancer of the tongue. Oral Oncol 40:532–537

    Article  CAS  PubMed  Google Scholar 

  26. Ekberg T, Nestor M, Engstrom M, Nordgren H, Wester K, Carlsson J, Anniko M (2005) Expression of EGFR, HER2, HER3, and HER4 in metastatic squamous cell carcinomas of the oral cavity and base of tongue. Int J Oncol 26:1177–1185

    CAS  PubMed  Google Scholar 

  27. Kuropkat C, Venkatesan TK, Caldarelli DD, Panje WR, Hutchinson J, Preisler HD, Coon JS, Werner JA (2002) Abnormalities of molecular regulators of proliferation and apoptosis in carcinoma of the oral cavity and oropharynx. Auris Nasus Larynx 29:165–174

    Article  PubMed  Google Scholar 

  28. Angiero F, Sordo RD, Dessy E, Rossi E, Berenzi A, Stefani M, Sidoni A (2008) Comparative analysis of c-erbB-2 (HER-2/neu) in squamous cell carcinoma of the tongue: does over-expression exist? And what is its correlation with traditional diagnostic parameters? J Oral Pathol Med 37:145–150

    Article  PubMed  Google Scholar 

  29. Freier K, Bosch FX, Flechtenmacher C, Devens F, Benner A, Lichter P, Joos S, Hofele C (2003) Distinct site-specific oncoprotein overexpression in head and neck squamous cell carcinoma: a tissue microarray analysis. Anticancer Res 23:3971–3977

    CAS  PubMed  Google Scholar 

  30. Erjala K, Sundvall M, Junttila TT, Zhang N, Savisalo M, Mali P, Kulmala J, Pulkkinen J, Grenman R, Elenius K (2006) Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells. Clin Cancer Res 12:4103–4111

    Article  CAS  PubMed  Google Scholar 

  31. Ongkeko WM, Altuna X, Weisman RA, Wang-Rodriguez J (2005) Expression of protein tyrosine kinases in head and neck squamous cell carcinomas. Am J Clin Pathol 124:71–76

    Article  CAS  PubMed  Google Scholar 

  32. Mărgăritescu C, Pirici D, Simionescu C, Stepan A (2011) The utility of CD44, CD117 and CD133 in identification of cancer stem cells (CSC) in oral squamous cell carcinomas (OSCC). Romanian J Morphol Embryol 52(3 Suppl):985–993

    Google Scholar 

  33. Chang BW, Kim DH, Kowalski DP, Burleson JA, Son YH, Wilson LD, Haffty BG (2004) Prognostic significance of cyclooxygenase-2 in oropharyngeal squamous cell carcinoma. Clin Cancer Res 10:1678–1684

    Article  CAS  PubMed  Google Scholar 

  34. Pannone G, Sanguedolce F, De Maria S, Farina E, Lo Muzio L, Serpico R, Emanuelli M, Rubini C, De Rosa G, Staibano S, Macchia L, Bufo P (2007) Cyclooxygenase isozymes in oral squamous cell carcinoma: a real-time RT-PCR study with clinic pathological correlations. Int J Immunopathol Pharmacol 20:317–324

    CAS  PubMed  Google Scholar 

  35. Atula T, Hedström J, Ristimäki A, Finne P, Leivo I, Markkanen-Leppänen M, Haglund C (2006) Cyclooxygenase-2 expression in squamous cell carcinoma of the oral cavity and pharynx: association to p53 and clinical outcome. Oncol Rep 16:485–490

    CAS  PubMed  Google Scholar 

  36. Ryott M, Marklund L, Wangsa D, Elmberger G, Munck-Wikland E (2011) Cyclooxygenase-2 expression in oral tongue squamous cell carcinoma. J Oral Pathol Med 40:385–389

    Article  CAS  PubMed  Google Scholar 

  37. Lang S, Tiwari S, Andratschke M, Loehr I, Lauffer L, Bergmann C, Mack B, Lebeau A, Moosmann A, Whiteside TL, Zeidler R (2007) Immune restoration in head and neck cancer patients after in vivo COX-2 inhibition. Cancer Immunol Immunother 56:1645–1652

    Article  CAS  PubMed  Google Scholar 

  38. Saba NF, Hurwitz SJ, Kono SA, Yang CS, Zhao Y, Chen Z, Sica G, Muller S, Moreno-Williams R, et al. (2014) Chemoprevention of head and neck cancer with celecoxib and erlotinib: results of a phase Ib and pharmacokinetic study. Cancer Prev Res 7:283–291

    Article  CAS  Google Scholar 

  39. Gross NB, Bauman JE, Godding WE, Denq W, Thomas SM, Wang L, Chiosea S, Hood BL, Flint MS, Sun M, et al. (2014) Erlotinib-erlotinib-sulindac vs placebo: a randomised, double-blind, placebo-controlled window trial in operable head and neck cancer. Clin Cancer Res 20:3289–3298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. De May RM (1996) The Art and Science of Cytopathology. ASCP Press 1st edition, USA, pp 329–330.

  41. Navone R, Pentenero M, Gandolfo S (2011) Liquid-based cytology in oral cavity squamous cell cancer. Curr Opin Otolaryngol Head Neck Surg 19:77–81

    Article  PubMed  Google Scholar 

  42. Malle D, Valeri RM, Photiou C, Kaplanis K, Andreadis C, Tsavdaridis D, Destouni C (2005) Significance of immunocytochemical expression of E-cadherin, N-cadherin and CD44 in serous effusions using liquid-based cytology. Acta Cytol 49:11–16

    Article  PubMed  Google Scholar 

  43. Schwartz JL, Panda S, Beam C, Bach LE, Adami GR (2008) RNA from brush oral cytology to measure squamous cell carcinoma gene expression. J Oral Pathol Med 37:70–77

    Article  CAS  PubMed  Google Scholar 

  44. Lothaire P, de Azambuja E, Dequanter D, Lalami Y, Sotiriou C, Andry G, Castro Jr G, Awada A (2006) Molecular markers of head and neck squamous cell carcinoma Promising signs in need of prospective evaluation. Head Neck 28:256–269

    Article  PubMed  Google Scholar 

  45. Simon RM, Paik S, Hayes DF (2009) Use of archived specimens in evaluation of prognostic and predictive biomarkers. J Natl Cancer Inst 101:1446–1452

    Article  PubMed  PubMed Central  Google Scholar 

  46. Maltby S, Freeman S, Gold MJ, Baker JHE, Minchinton AI, Gold MR, Roskelley CD, McNagny KM (2011) Opposing roles for CD34 in B16 melanoma tumor growth alter early stage vasculature and late stage immune cell infiltration. PLoS One 6(4):e18160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Saura C, Baselga J, Herbst R, del Campo J, Marotti M, Tessier J, Collins B, Heymach J (2009) Antitumor activity of cediranib in patients with metastatic or recurrent head and neck cancer (HNC) or recurrent non-small cell lung cancer (NSCLC). an open-label exploratory study. J Clin Oncol 27(15S):6023

    Google Scholar 

  48. Machiels J, Haddad RI, Fayette J, Licitra L, Tahara M, Vermorken JB, Clement PM, Gauler T, Cupissol D, Grau JJ, Guigay J, Caponigro F, De Castro Jr G, De Souza VL, Keilholz U, Del Campo J, Cong X, Ehmrooth E, Cohen EE (2015) Afatinib versus methotrexate as second-line treatment for patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol 16:583–594

    Article  CAS  PubMed  Google Scholar 

  49. de Souza JA, Davis DW, Zhang Y, Khattri A, Seiwert TY, Aktolga S, Wong SJ, Kozloff MF, Nattam S, Lingen MW, Kunnavakkam R, Stenson KM, Blair EA, Bozeman J, Dancey JE, Vokes EE, Cohen EE (2012) A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 18:2336–2243

    Article  PubMed  PubMed Central  Google Scholar 

  50. Vermorken JB, Peyrade F, Krauss J, Mesía R, Remenar E, Gauler TC, Keilholz U, Delord JP, Schafhausen P, Erfán J, Brümmendorf TH, Iglesias L, Bethe U, Hicking C, Clement PM (2014) Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part). Ann Oncol 25:682–688

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Fruh M, Pless M (2012) EGFR IHC score for selection of cetuximab treatment: ready for clinical practice? Transl Lung Cancer Res 1:145–146

    PubMed  PubMed Central  Google Scholar 

  52. Lynch T, Bhagavatheeswaran P, Mukhopadyay P (2011) A retrospective subgroup analysis of EGFR immunohistochemistry expression by histo-score correlated to outcomes from the BMS099 1st line phase III NSCLC trial of cetuximab plus carboplatin/taxane. Eur J Cancer 47:S591–S592

    Article  Google Scholar 

  53. Han XJ, Sun LF, Nishiyama Y, Feng B, Michiue H, Seno M, Matsui H, Tomizawa K (2013) Theranostic protein targeting ErbB2 for bioluminescence imaging and therapy for cancer. PLoS One 8:e75288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Muthu MS, Tai Leong D, Mei L, Feng SS (2014) Nanotheranostics ˗ application and further development of nanomedicine strategies for advanced theranostics. Theranostics 4:660–677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Petros Zikos for his help in data collection.

Author information

Authors and Affiliations

  1. Department of Cancer Medicine, Gustave Roussy, Cancer Campus, Grand Paris, 114 rue Edouard Vaillant, 94805, Villejuif, France

    Anna Patrikidou

  2. Department of Cytopathology, “Theagenio” Cancer Hospital, Thessaloniki, Greece

    Rosalia Maria Valeri & Charikleia Destouni

  3. Department of Oral and Maxillofacial Surgery, “Theagenio” Cancer Hospital, Thessaloniki, Greece

    Konstantinos Vahtsevanos

  4. Department of Forestry and Management of the Environment and Natural Resources, School of Agricultural Sciences and Forestry, Democritus University, Alexandroupoli, Greece

    Kyriaki Kitikidou

Authors
  1. Anna Patrikidou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rosalia Maria Valeri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kyriaki Kitikidou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charikleia Destouni
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Konstantinos Vahtsevanos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anna Patrikidou.

Ethics declarations

Conflict of Interest

The authors have no conflicts of interest to declare.

Funding Information

No specific funding was available for this project.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Patrikidou, A., Valeri, R.M., Kitikidou, K. et al. Introducing Cytology-Based Theranostics in Oral Squamous Cell Carcinoma: A Pilot Program. Pathol. Oncol. Res. 22, 401–411 (2016). https://doi.org/10.1007/s12253-015-0017-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-015-0017-6

Keywords

Search

Navigation