Elsevier

Auris Nasus Larynx

Volume 31, Issue 4, December 2004, Pages 417-424
Auris Nasus Larynx

Prognostic significance of EGF receptor expression in early glottic cancer

https://doi.org/10.1016/j.anl.2004.05.003Get rights and content

Abstract

Objective: A positive relationship between epidermal growth factor receptor (EGFR) expression and radioresistance has been shown both in vitro and in vivo. In a group of 31 patients with early glottic cancer treated with definitive radiotherapy, the relationship of EGFR expression with patient and tumor related parameters were analyzed and the prognostic effect of EGFR expression on local control (LC) was assessed. Material and method: Between 1991 and 2001, 114 patients with early glottic (Tis-T2N0M0) squamous cell carcinoma were treated with radiotherapy at our institution. Among these, 31 patients whose pretreatment pathology specimens were available for immunohistochemical analysis formed the study population. Median age was 64 (46–77). Anterior commissure involvement was evident in 12 (38.7%) patients. Distribution according to T stage was as follows: Tis 6 (19.3%), T1 22 (71%), and T2 3 (9.7%). Histopathological grades of the 25 T1-2 tumors were 10/25 (40%) grade 1, 9/25 (36%) grade 2 and 6/25 (24%) grade 3. Our radiotherapy regimen was 66–70 Gy in 33–35 fractions over 6.5–7 weeks. The median follow-up period was 45 months (range, 5–116). Following immunohistochemical staining, quantitative immunohistochemistry (IHC) was performed by image analysis software and stained tumoral area percentage (STAP) was identified. The cut-off value was ≤5% versus >5%. The relationship of EGFR expression with patient (age) and tumor related (T stage, histopathological grade, and anterior commissure involvement) parameters was evaluated using chi-square test. Prognostic significance of EGFR expression, age, T stage, histopathological grade, and anterior commissure involvement on LC was assessed using log-rank test. Results: No difference was found in EGFR content distribution in relation to age, T stage, histopathological grade, and anterior commissure involvement. In the univariate analysis including age (≤60 versus >60), T stage (Tis and T1 versus T2), histopathological grade (grade 1 and 2 versus grade 3), anterior commissure involvement (present versus absent), and EGFR expression (high versus low), only T stage and EGFR expression were found to be significant prognostic factors affecting LC (P = 0.0006 and P = 0.03, respectively). Conclusion: The results of this series support that EGFR expression is an unfavorable prognostic factor in early glottic carcinomas. For this reason EGFR IHC may be considered for selecting patients for more aggressive therapies (radiotherapy with different fractionation schemes or surgery) or enrollment into trials targeting EGFR signaling pathways.

Introduction

Early glottic cancer is a curable disease with high local control (LC) rates using either definitive radiotherapy or surgery [1], [2]. Following definitive radiotherapy, 5 year initial LC rate for T1 glottic squamous cell carcinoma is in the range of 80–95%, and 50–85% for T2 [3], [4], [5], [6], [7]. After local failure, ultimate 5-year LC rates of 90–100% can be achieved through the use of salvage surgery [8], [9].

Several prognostic factors affecting LC have been reported including age, gender, stage, histology, involvement of anterior commissure, dose per fraction, total dose, overall treatment time, treatment energy, field size, and pre-radiotherapy hemoglobin level. In addition, the prognostic significance of novel biological factors has also been studied. In this context, several studies have focused also on the role of epidermal growth factor (EGF) in the onset and prognosis of various cancers including head and neck [10], [11], [12], [13], [14], [15], [16].

EGF is a polypeptide that acts through a specific trans-membrane receptor (EGFR) and exerts mitogenic activity on several normal and neoplastic cell lines, including laryngeal cancer cells [14]. EGFR is a 170 kDa membrane-spanning glycoprotein, encoded by c-erbB1 proto-oncogene [17], [18]. It is a tyrosine kinase receptor which has extracellular ligand-binding amino-terminal and cytoplasmic carboxy-terminal domains [18]. EGF, transforming growth factor-α and amphiregulin are the ligands for EGFR [17], [18]. Ligand binding to EGFR and receptor dimerisation causes autophosphorylation and/or cross-phosphorylation of several tyrosine residues, which in turn initiate intracellular signaling cascade [18]. EGFR signal transduction, which acts through altered gene expression, ultimately results in increased proliferation, angiogenesis, differentiation and decreased apoptosis [17], [18].

EGFR expression was found to be significantly higher in laryngeal tumors than in normal mucosa, suggesting that EGFR may induce the growth of laryngeal cancer cells [15], [16]. Grandis et al. found that EGFR staining intensity of squamous cell carcinoma of head and neck tissues increased with higher degrees of dysplasia and closer proximity to the tumor [19].

EGFR expression has been evaluated as a prognostic factor in head and neck carcinoma series which included laryngeal cancer [20], [21], [22]. These series were heterogeneous in terms of stage distribution including both early and advanced stage head and neck cancers. It is known that early glottic carcinoma is a distinct entity that necessitates therapeutic approaches quite different from other laryngeal carcinomas. A positive relationship between EGFR expression and radioresistance has been shown both in vitro [23] and in vivo [24]. However, only three studies have examined the relationship between EGFR expression and LC of early glottic cancer as a primary endpoint [13], [25], [26].

In this study, EGFR expression has been retrospectively evaluated in a group of early glottic cancer patients treated with a consistent definitive radiotherapy regimen whose pretreatment pathology specimens were available for staining. The method of choice was quantitative IHC. The relationship of EGFR expression with patient and tumor related parameters was analyzed and the prognostic significance of EGFR expression with respect to LC was assessed.

Section snippets

Material and method

Between 1991 and 2001, 114 patients with early glottic (Tis-T2N0M0) squamous cell carcinoma were treated with definitive radiotherapy at our institution. Five-year LC rate was 84.2%, and ultimate 5-year LC rate was 96.9% following salvage treatments. Among these 114 patients, 31 patients whose pretreatment pathology specimens were available for immunohistochemical analysis formed the study population.

There were 30 males. The median age was 64 (46–77). All patients were staged according to the

EGFR expression and relationship with patient and tumor related parameters

Five of the 31 patients (16.1%) had EGFR values greater than 5%. Table 2 demonstrates both the distribution of and the results of the analysis of EGFR expression according to patient and tumor related parameters. No difference was found in EGFR content distribution in relation to age, T stage, and histopathological grade or anterior commissure involvement.

EGFR expression and local control

Ten patients (32.3%) had a local recurrence. Three and 5-year LC rates were 74% and 60%, respectively. Three-year LC rates were 30% in the

Discussion

Definitive radiotherapy causes 5 year initial LC rates for T1 and T2 glottic squamous cell cancer in the range of 80–95% and 50–85%, respectively [3], [4], [5], [6], [7]. There is a large variation in the initial LC rates for early glottic cancer treated with definitive radiotherapy. This variation also is relevant for the patients whose tumors are the same stage. A number of studies have identified patient (age, gender, pre-radiotherapy hemoglobin level), tumor (histology, involvement of

Acknowledgements

We would like to thank Rachel Ann Cooper Sen, MRCP, FRCR, MD for her kind help in checking of grammer.

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