Prognostic impact of p53, c-erbB-2 and epidermal growth factor receptor on head and neck carcinoma
Keywords:
Squamous cell carcinoma, Genes p53, Genes c-erbB-2, Protein p53, Protein c-erbB-2Abstract
CONTEXT: p53, c-erbB-2 and epidermal growth factor receptor (EGFR) are cancer-related proteins that are usually expressed in head and neck squamous cell carcinoma (SCC). Their prognostic value remains controversial. OBJECTIVE: To evaluate the prognostic impact of p53, c-erbB-2 and EGFR expression in head and neck SCC. TYPE OF STUDY: Prospective. SETTING: Head and Neck Surgery Department, Hospital AC Camargo, São Paulo. METHODS: Fifty-four patients were studied for p53, cerbB-2 and EGFR expression in head and neck SCC and adjacent mucosa, via immunohistochemistry. These data were correlated with histoclinical data and survival. RESULTS: There was a direct association of p53 expression in SCC and mucosa (p = 0.001); loss of c-erbB-2 expression (-) from normal mucosa to SCC (p = 0.04); lower frequency of association of c-erbB-2 (+) with EGFR (-) in SCC (p = 0.02); and a direct association of EGFR (+) expression in SCC and mitotic index (p = 0.03). The 60-month actuarial survival rates for patients presenting lymph node metastasis were higher when there was no capsule rupture by SCC (48.3%; p = 0.02), no more than one positive lymph node (52.3%; p = 0.004) or clear surgical margins (47.0%; p = 0.01), in comparison with patients presenting capsule rupture (20.2%), two or more positive lymph nodes (18.7%) or compromised surgical margins (0.0%), respectively. Patients presenting SCC p53 (+) and EGFR (-) demonstrated greater survival (75.0%; p = 0.03) than for the remaining group (33.1%). Multivariate analysis confirmed the positive impact of p53 (+) and EGFR (-) on survival (p = 0.02). DISCUSSION: Associations were found for p53, cerbB-2 and EGFR expression with histoclinical data and prognosis. Interestingly, these results suggest that loss of mucosal c-erbB-2 expression could be involved in SCC carcinogenesis; EGFR expression in SCC is related to tumor mitotic index; and presence of p53 with absence of EGFR expression in head and neck SCC may be a prognostic factor for survival. CONCLUSIONS: Further prospective studies should be conducted to confirm the influence of p53, c-erbB-2 and EGFR on histoclinical data and prognosis.
Downloads
References
Nees M, Homann N, Discher H, et al. Expression of mutated p53 occurs in tumor-distant epithelia of head and neck cancer patients: a possible molecular basis for the development of multiple tumors. Cancer Res. 1993;53(18):4189-96.
Shin DM, Charuruks N, Lippman SM, et al. p53 protein accumulation and genomic instability in head and neck multistep tumorigenesis. Cancer Epidemiol Biomarkers Prev. 2001;10(6):603-9.
Rowley H, Helliwell TR, Jones AS, Roland NJ, Field EA, Field JK. An immunohistochemical analysis of p53 protein expression in pre-malignant and malignant tissues of the oral cavity. Clin Otolaryngol. 1997;22(1):23-9.
Kilpi A, Rich AM, Konttinen YT, Reade PC. Expression of c- erbB-2 protein in keratinocytes of oral mucosal lichen planus and subsequent squamous cell carcinoma. Eur J Oral Sci. 1996;104(3):278-84.
Xia W, Lau YK, Zhang HZ, et al. Strong correlation between c-erbB-2 overexpression and overall survival of patients with oral squamous cell carcinoma. Clin Cancer Res. 1997;3(1):3-9.
Schnürch HG, Stegmüller M, Vering A, Beckmann MW, Bender HG. Growth inhibition of xenotransplanted human carcinomas by a monoclonal antibody directed against the epidermal growth factor receptor. Eur J Cancer. 1994;30A(4):491-6.
Chakrabarty S, Rajagopal S, Huang S. Expression of antisense epidermal growth factor receptor RNA downmodulates the malignant behavior of human colon cancer cells. Clin Exp Metastasis. 1995;13(3):191-5.
Rusch V, Klimstra D, Linkov I, Dmitrovsky E. Aberrant expres- sion of p53 or the epidermal growth factor receptor is frequent in early bronchial neoplasia and coexpression precedes squamous cell carcinoma development. Cancer Res. 1995;55(6):1365-72.
Maiorano E, Botticella MA, Marzullo A, Resta L. Expression of ER-D5 and EGFr in laryngeal carcinoma and pre-malignant epithelium. Acta Otolaryngol Suppl. 1997;527:95-9.
O-charoenrat P, Rhys-Evans PH, Archer DJ, Eccles SA. C-erbB receptors in squamous cell carcinomas of the head and neck: clinical significance and correlation with matrix metallopro- teinases and vascular endothelial growth factors. Oral Oncol. 2002;38(1):73-80.
Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981;29(4):577-80.
Ball VA, Righi PD, Tejada E, Radpour S, Pavelic ZP, Gluckman JL. p53 immunostaining of surgical margins as a predictor of local recurrence in squamous cell carcinoma of the oral cavity and oropharynx. Ear Nose Throat J. 1997;76(11):818-23.
Wilkman TS, Hietanen JH, Malmström MJ, Konttinen YT. Immunohistochemical analysis of the oncoprotein c-erbB-2 expression in oral benign and malignant lesions. Int J Oral Maxillofac Surg. 1998;27(3):209-12.
Weidner U, Peter S, Strohmeyer T, Hussnätter R, Ackermann R, Sies H. Inverse relationship of epidermal growth factor receptor and HER2/neu gene expression in human renal cell carcinoma. Cancer Res. 1990;50(15):4504-9.
Gulliford TJ, Huang GC, Ouyang X, Epstein RJ. Reduced ability of transforming growth factor-alpha to induce EGF receptor heterodimerization and downregulation suggests a mechanism of oncogenic synergy with ErbB2. Oncogene. 1997;15(18):2219-23.
Grandis JR, Tweardy DJ, Melhem MF. Asynchronous modula- tion of transforming growth factor alpha and epidermal growth factor receptor protein expression in progression of premalignant lesions to head and neck squamous cell carcinoma. Clin Cancer Res. 1998;4(1):13-20.
Rowley H, Roland NJ, Helliwell TR, Caslin A, Kinsella AR, Jones AS. p53 protein expression in tumors from head and neck subsites, larynx and hypopharynx, and differences in relationship to survival. Clin Otolaryngol. 1998;23(1):57-62.
Fan Z, Mendelsohn J. Therapeutic application of anti-growth fac- tor receptor antibodies. Curr Opin Oncol. 1998;10(1):67-73.
Bier H, Hoffmann T, Haas I, van Lierop A. Anti-(epidermal growth factor) receptor monoclonal antibodies for the induc- tion of antibody-dependent cell-mediated cytotoxicity against squamous cell carcinoma lines of the head and neck. Cancer Immunol Immunother. 1998;46(3):167-73.
Grandis JR, Zeng Q, Drenning SD, Tweardy DJ. Normatization of EGFR mRNA levels following restoration of wild-type p53 in a head and neck squamous cell carcinoma cell line. Int J Oncol.1998;13(2):375-8.
Grandis JR, Chakraborty A, Zeng Q, Melhem, MF, Tweardy DJ. Downmodulation of TGF-alpha protein expression with antisense oligonucleotides inhibits proliferation of head and neck squamous carcinoma but not normal mucosal epithelial cells. J Cell Biochem. 1998;69(1):55-62.
Sauter ER, Ridge JA, Gordon J, Eisenberg BL. p53 overexpression correlates with increased survival in patients with squamous cell carcinoma of the tongue base. Am J Surg. 1992;164(6):651-3.
Chomchai JS, Du W, Sarkar FH, et al. Prognostic significance of p53 gene mutations in laryngeal cancer. Laryngoscope. 1999;109(3):455-9.
Nicholson RI, Gee JM, Harper ME. EGFR and cancer prog- nosis. Eur J Cancer. 2001;37(Suppl 4):S9-15.
