Document Type : Original Article

Authors

1 Associate Professor of Oral and Maxillofacial Medicine , Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

2 Associate Professor, Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Professor of Oral and Maxillofacial Medicine, Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

4 Professor of Oral and Maxillofacial pathology, Dental Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

5 Specialist of Cosmetic and Restorative Dentistry, Tehran, Iran

Abstract

Background:Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity. Despite some improvements in treatment, the survival rate is still very low, mainly due to the possible development of secondary malignancy or metastasis. Clinical and pathological features as well as molecular biomarkers might predict the recurrence.
In recent years, many studies have been carried out on molecular biomarkers that can predict the prognosis of OSCC. One of these markers is the epidermal growth factor receptor (EGFR), which has led to different results. The aim of this study was to determine EGFR level in OSCC and to analyze its correlation with clinicopathological features.
Methods: A total of 62 paraffin-embedded samples from OSCC patients treated in the oncology department of the Omid Hospital in the city of Mashhad, Iran were selected and EGFR staining was performed. The clinical and histopathological data were extracted from the medical records.
Results: EGFR expression was positive in 98.4% of the cases. There was a significant difference between EGFR expression in the tumor and control cases in terms of cellularity and intensity (p˂0.001 and p=0.004, respectively). No statistically significant correlation was observed between EGFR and clinicopathological parameters. There was also no significant relationship between the cellularity and intensity expression of EGFR and patient survival (p=0.92 and p=0.42, respectively).
Conclusion: In view of the high EGFR expression in squamous cell carcinoma, further studies on the role of EGFR in cell processes such as proliferation, angiogenesis and differentiation of the tumor are recommended.

Keywords

  1. Jonsson EL, Nylander K, Hallen L, Laurell G. Effect of radiotherapy on expression of hyaluronan and EGFR and presence of mast cells in squamous cell carcinoma of the head and neck. Oncol Lett 2012; 4(6):1177-82.
  2. Nagano H, Tomida C, Yamagishi N, Teshima-Kondo S. VEGFR-1 Regulates EGF-R to Promote Proliferation in Colon Cancer Cells. Int J Mol Sci 2019; 20(22):5608.
  3. Hao C, Li Z, Zhang X, Zhang H, Shang H, Bao J, et al. Expression and clinical significance of EGF and TGF-α in chronic pancreatitis and pancreatic cancer. Minerva Endocrinol 2018; 43(3):253-8.
  4. Abedi-Ardekani B, Dar NA, Mir MM, Zargar SA, Lone MM, Martel-Planche G, et al. Epidermal growth factor receptor (EGFR) mutations and expression in squamous cell carcinoma of the esophagus in central Asia. BMC Cancer 2012; 12:602.
  5. Xu Q, Zhang Q, Ishida Y, Hajjar S, Tang X, Shi H, et al. EGF induces epithelial-mesenchymal transition and cancer stem-like cell properties in human oral cancer cells via promoting Warburg effect. Oncotarget 2017; 8(6):9557-71.
  6. Al-Momani H, Barnes R, El-Hadi A, Shah R, Lewis WG, Edwards P. Human epidermal growth factor receptor-2 in oesophageal cancers: an observational study. World J Gastroenterol 2012; 18(44):6447-51.
  7. Yoshikawa H, Ehrhart EJ, Charles JB, Thamm DH, Larue SM. Immunohistochemical characterization of feline oral squamous cell carcinoma. Am J Vet Res 2012; 73(11):1801-6.
  8. Lin JS, Sun FJ, Lin PY, Chang KW, Yang CC, Liu CJ. Clinicopathological and prognostic significance of preoperative serum epidermal growth factor levels in patients with oral squamous cell carcinoma. Int J Oral Maxillofac Surg 2018; 47(10):1236-42.
  9. Pedicini P, Nappi A, Strigari L, Alicia Jereczek-Fossa B, Alterio D, Cremonesi M, et al. Correlation between egfr expression and accelerated proliferation during radiotherapy of head and neck squamous cell carcinoma. Radiat Oncol 2012; 7:143.
  10. Prasad R, Katiyar SK. Bioactive phytochemical proanthocyanidins inhibit growth of head and neck squamous cell carcinoma cells by targeting multiple signaling molecules. PLoS One 2012; 7(9):e46404.
  11. Wu SG, Chang YL, Lin JW, Wu CT, Chen HY, Tsai MF, et al. Including total EGFR staining in scoring improves EGFR mutations detection by mutation-specific antibodies and EGFR TKIs response prediction. PLoS One 2011; 6(8):e23303.
  12. Benson J, Chen Y, Cornell-Kennon SA, Dorsch M, Kim S, Leszczyniecka M, et al. Validating cancer drug target. Nature 2006; 441(7092):451-6.
  13. Nafarzadeh S, Moshref M, Mashhadi Abbas F, Mohammad Taheri Z. Correlation between expression of EGFR and Laminin–5 with clinical stage and microscopic grade of oral squamous cell carcinoma. Shahid Beheshti University Dental Journal 2009; 27(1):43-7. [In Persian].
  14. Nafarzadeh S, Moshref M, Mashhadi Abbass F, Mohammad Taheri Z, Poorsattar Bejeh Mir A. Predictive value of epidermal growth factor (EGF) and laminin-5 for clinicopathologic oral squamous cell carcinoma (OSCC) staging and grading in Iranian population. Medical Journal of The Islamic Republic of Iran 2010; 24(3): 146-50.
  15. Sebastian S, Settleman J, Reshkin SJ, Azzariti A, Bellizzi A, Paradiso A. The complexity of targeting EGFR signalling in cancer: from expression to turnover. Biochim Biophys Acta 2006; 1766(1):120-39.
  16. Morgan S, Grandis JR. ErbB receptors in the biology and pathology of the aerodigestive tract. Exp Cell Res 2009; 315(4):572-82.
  17. Hiraishi Y, Wada T, Nakatani K, Negoro K, Fujita S. Immunohistochemical expression of EGFR and p-EGFR in oral squamous cell carcinomas. Pathol Oncol Res 2006; 12(2):87-91.
  18. Mendelsohn J. The epidermal growth factor receptor as a target for cancer therapy. Endocr Relat Cancer 2001; 8(1):3-9.
  19. Laimer K, Spizzo G, Gastl G, Obrist P, Brunhuber T, Fong D, et al. High EGFR expression predicts poor prognosis in patients with squamous cell carcinoma of the oral cavity and oropharynx: a TMA-based immunohistochemical analysis. Oral Oncol 2007; 43(2):193-8.
  20. Kuttan NA, Bhakthan NM. Epidermal growth factor receptor (EGFR) in oral squamous cell carcinomas: overexpression, localization and therapeutic implications. Indian J Dent Res 1997; 8(1):9-18.
  21. Gonzaga IM, Soares-Lima SC, de Santos PT, Blanco TC, de Reis BS, Quintella DC, et al. Alterations in epidermal growth factor receptors 1 and 2 in esophageal squamous cell carcinomas. BMC Cancer 2012; 12:569.
  22. Sunpaweravong P, Suwiwat S, Sunpaweravong S, Puttawibul P, Mitarnun W. Correlation of epidermal growth factor receptor mutation, immunohistochemistry, and fluorescence in situ hybridization in esophageal squamous cell carcinoma. J Med Assoc Thai 2009; 92(9):1136-42.
  23. Hanawa M, Suzuki S, Dobashi Y, Yamane T, Kono K, Enomoto N, et al. EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus. Int J Cancer 2006; 118(5):1173-80.
  24. Zuo JH, Zhu W, Li MY, Li XH, Yi H, Zeng GQ, et al. Activation of EGFR promotes squamous carcinoma SCC10A cell migration and invasion via inducing EMT-like phenotype change and MMP-9-mediated degradation of E-cadherin. J Cell Biochem 2011; 112(9):2508-17.
  25. Storkel S, Reichert T, Reiffen KA, Wagner W. EGFR and PCNA expression in oral squamous cell carcinomas--a valuable tool in estimating the patient's prognosis. Eur J Cancer B Oral Oncol 1993; 29B(4):273-7.
  26. Bernardes VF, Gleber-Netto FO, Sousa SF, Silva TA, Aguiar MC. Clinical significance of EGFR, Her-2 and EGF in oral squamous cell carcinoma: a case control study. J Exp Clin Cancer Res 2010; 29(1):40.
  27. Eriksen JG, Steiniche T, Askaa J, Alsner J, Overgaard J. The prognostic value of epidermal growth factor receptor is related to tumor differentiation and the overall treatment time of radiotherapy in squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys 2004; 58(2):561-6.
  28. Serilmez M, Ozgur E, Karaman S, Gezer U, Duranyıldız D. Detection of serum protein and circulating mRNA of cMET, HGF EGF and EGFR levels in lung cancer patients to guide individualized therapy. Cancer Biomark 2019; 25(2):177-84.
  29. Chuang CY, Chen MK, Hsieh MJ, Yeh CM, Lin CW, Yang WE, et al. High level of plasma EGFL6 is associated with clinicopathological characteristics in patients with oral squamous cell carcinoma. Int J Med Sci 2017; 14(5):419-24.
  30. Ulanovski D, Stern Y, Roizman P, Shpitzer T, Popovtzer A, Feinmesser R. Expression of EGFR and Cerb-B2 as prognostic factors in cancer of the tongue. Oral Oncol 2004; 40(5):532-7.
  31. Mahipa A, Mcdonald M, Witkiewicz A, Carr BI. Cell membrane and cytoplasmic epidermal growth factor receptor expression in pancreatic ductal adenocarcinoma. Med Oncol 2011; 29(1):134-9.
  32. Kong Q, Majeska RJ, Vazquez M. Migration of connective tissue-derived cells is mediated by ultra-low concentration gradient fields of EGF. Exp Cell Res 2011; 317(11):1491-502.
  33. Diniz-Freitas M, Garcia-Caballero T, Antunez-Lopez J, Gandara-Rey JM, Garcia-Garcia A. Pharmacodiagnostic evaluation of EGFR expression in oral squamous cell carcinoma. Oral Dis 2007; 13(3):285-90.
  34. Sarkis SA, Abdullah BH, Abdul Majeed BA, Talabani NG. Immunohistochemical expression of epidermal growth factor receptor (EGFR) in oral squamous cell carcinoma in relation to proliferation, apoptosis, angiogenesis and lymphangiogenesis. Head Neck Oncol 2010; 2:13.
  35. Bentzen SM, Atasoy BM, Daley FM, Dische S, Richman PI, Saunders MI, et al. Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial. J Clin Oncol 2005; 23(24):5560-7.
  36. Chung CH, Ely K, McGavran L, Varella-Garcia M, Parker J, Parker N, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol 2006; 24(25):4170-6.
  37. Licitra L, Mesia R, Rivera F, Remenar E, Hitt R, Erfan J, et al. Evaluation of EGFR gene copy number as a predictive biomarker for the efficacy of cetuximab in combination with chemotherapy in the first-line treatment of recurrent and/or metastatic squamous cell carcinoma of the head and neck: EXTREME study. Ann Oncol 2011; 22(5):1078-87.
  38. Kanematsu T, Yano S, Uehara H, Bando Y, Sone S. Phosphorylation, but not overexpression, of epidermal growth factor receptor is associated with poor prognosis of non-small cell lung cancer patients. Oncol Res 2003; 13(5):289-98.
  39. Gao J, Ulekleiv CH, Halstensen TS. Epidermal growth factor (EGF) receptor-ligand based molecular staging predicts prognosis in head and neck squamous cell carcinoma partly due to deregulated EGF- induced amphiregulin expression. J Exp Clin Cancer Res 2016; 35(1):151.
  40. Smid EJ, Stoter TR, Bloemena E, Lafleur MV, Leemans CR, Van Der Waal I, et al. The importance of immunohistochemical expression of EGFr in squamous cell carcinoma of the oral cavity treated with surgery and postoperative radiotherapy. Int J Radiat Oncol Biol Phys 2006; 65(5):1323-9.
  41. Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer 2001; 37(Suppl 4):S3-8.
  42. Zhao L, He LR, Xi M, Cai MY, Shen JX, Li QQ, et al. Nimotuzumab promotes radiosensitivity of EGFR-overexpression esophageal squamous cell carcinoma cells by upregulating IGFBP-3. J Transl Med 2012; 10:249.
  43. Lo WL, Kao SY, Chi LY, Wong YK, Chang RC. Outcomes of oral squamous cell carcinoma in Taiwan after surgical therapy: factors affecting survival. J Oral Maxillofac Surg 2003; 61(7):751-8.
  44. Nguyen TV, Yueh B. Weight loss predicts mortality after recurrent oral cavity and oropharyngeal carcinomas. Cancer 2002; 95(3):553-62.
  45. Chen IH, Chang JT, Liao CT, Wang HM, Hsieh LL, Cheng AJ. Prognostic significance of EGFR and Her-2 in oral cavity cancer in betel quid prevalent area cancer prognosis. Br J Cancer 2003; 89(4):681-6.