Clinical Investigations
Overexpression of p53 Protein Does Not Predict Local-Regional Control or Survival in Patients With Early-Stage Squamous Cell Carcinoma of the Glottic Larynx Treated With Radiotherapy

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Abstract

Purpose: Nonfunctional or mutated p53 protein (m-p53) is found in a myriad of solid tumors in humans. m-p53 is believed to confer radioresistance through inhibition of radiation-induced apoptosis. This study was carried out to determine if the overexpression of p53 in squamous cell carcinomas (SCC) of the glottic larynx treated with radiation therapy alone carried a poorer prognosis than normal wild-type p53 (w-p53) and could, therefore, be used as a marker of radioresistance in glottic SCC.

Methods & Materials: Eighty-six patients with early-stage glottic SCC (64 T1N0, 25 T2N0 by TMN stage) treated with contemporary radiotherapy techniques to doses of 50–70 Gy were analyzed. Aberrant p53 protein was detected by immunohistochemical (IHC) staining on archival tissue samples containing original tumor specimens. Analysis of prognostic factors and treatment outcome to expression of p53 was performed. All patients were carefully selected to have comparable sites of disease, histology, early-stage disease, and treatment delivered, thus increasing the power of this study by controlling for other independent factors affecting outcome.

Results: Sixty percent of patients demonstrated overexpression of p53 in tissue samples. Accumulation of p53 was not predictive of tumor grade, stage, or smoking status prior to diagnosis. p53 status was not predictive of treatment outcome parameters including local-regional failure rate and disease-free survival rate. Factors significantly affecting treatment outcome were stage and dose of radiotherapy in T2 patients (50 Gy vs. > 62 Gy).

Conclusion: m-p53 protein detected by IHC staining was not predictive as a prognostic factor for clinical outcome following radiation therapy for early-stage glottic SCC. This is in general agreement with other recently published studies of laryngeal carcinoma patients treated with radiation or surgery. At the present time, p53 status should not be used as a marker for prognosis and clinical outcome in laryngeal SCC.

Introduction

Squ amous cell carcinoma (SCC) of the larynx, when diagnosed at an early stage, is a highly curable disease. Radiation therapy is indicated for early-stage invasive glottic carcinoma in most cases. Excellent local-regional control and cause-specific survival rates are observed with radiation therapy [1]. There is, however, a subset of patients who fail radiation treatment. Although a good percentage of these cases can be surgically salvaged, the added morbidity and cost of a laryngectomy procedure following a full course of radiation therapy adversely impacts on patient quality of life. Treatment factors that affect outcome include radiation fraction size, total dose, technique, and overall treatment time 2, 3, 4, 5, 6. Stage and bulk of disease are well-known tumor-related factors predictive of outcome. The intent of this study was to search for other tumor-related factors that may identify patients at risk for failure to radiation therapy. We, therefore, embarked upon studying the prognostic significance of abnormal p53 tumor-suppressor gene expression in early-stage glottic SCC.

The p53 gene has been extensively studied and represents the most common mutated gene in human malignancies, including SCC of the head and neck mucosal sites. Normally functioning wild-type p53 protein (w-p53) possesses cell regulatory functions, including apoptosis, which has been shown to be an important pathway for tumor cell death following exposure to therapeutic radiation 7, 8. The protein product derived from mutated p53 (m-p53) gene is nonfunctional and blocks cells from undergoing apoptosis following irradiation. These cells continue to proliferate, despite injury due to ionizing radiation. Consequently, tumor cells that possess m-p53 are believed to be more radioresistant than those with w-p53. Aberrant p53 can be detected by several methods, including DNA sequencing and immunohistochemical staining with specific commercially prepared antihuman p53 monoclonal antibodies. The latter represents a relatively inexpensive and rapid technique. Malignant cells possessing abnormal p53 protein will stain positive owing to the fact that m-p53 protein has a longer half-life than w-p53 and, thus, stains more readily.

The purpose of this study was to determine whether or not the expression of aberrant p53 was predictive of local-regional control and survival for early-stage glottic SCC treated with radiation therapy. In comparison to previous studies investigating the significance of p53 overexpression, possible confounding factors were controlled for by selecting patients with similarly staged head and neck cancer from one specific site who were treated in a uniform fashion with radiotherapy in this study.

Section snippets

Patients

The medical records of 86 patients with early-stage (TMN Stage T1N0M0, T2N0M0) SCC of the glottic larynx who were treated with radiation therapy alone at the Sir Mortimer B. Davis - Jewish General Hospital between December 1978 and June 1995 were retrospectively reviewed. Patients were grouped according to stage (I vs. II). Patient and tumor characteristics are listed in Table 1.

Immunohistochemistry

Archival tissue samples retrieved from paraffin blocks processed at the time of diagnosis were cut, mounted on

Results

Cell nuclei staining positive for p53 (indicating presence of abnormal p53 protein) was noted in 60% (52 of 86) of patients. As shown in Table 1 p53 expression (negative vs. positive) was not predictive of T-stage (T1 vs. T2) or smoking status by Fisher’s exact test with p values of 0.81 and 0.47, respectively. Chi-squared test for independence revealed that m-p53 status (negative vs. positive) did not predict histological grade (p = 0.65).

Dose was found to be a significant factor affecting

Discussion

The presence of nonfunctional p53 is unquestionably a marker of abnormal cell population. The presence of mutated p53 (m-p53) has also been shown to be of prognostic significance in certain human tumor lines, such as transitional cell carcinoma of the bladder, locally advanced adenocarcinoma of the colon, and prostate adenocarcinoma 12, 13, 14. Whether or not the presence of m-p53 is a prognostic factor in head and neck SCC remains undefined. Studies supporting this hypothesis include those of

Acknowledgements

We are extremely grateful to Martine Bourdeau for her technical assistance.

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