Elsevier

Human Pathology

Volume 33, Issue 1, January 2002, Pages 105-110
Human Pathology

Original Contributions
Prognostic value of immunohistochemical expressions of p53, HER-2/neu, and bcl-2 in stage I non–small-cell lung cancer*

Presented at the United States and Canadian Academy of Pathology Meeting, New Orleans, LA, March 25-31, 2000.
https://doi.org/10.1053/hupa.2002.30183Get rights and content

Abstract

The outcomes of patients with stage I non–small-cell lung cancer (NSCLC) vary greatly, with a 5-year survival rate of approximately 60%. This study evaluated a number of molecular markers that may aid in predicting prognosis in stage I NSCLC after surgical resection. Immunohistochemical (IHC) staining of p53, HER-2/neu, bcl-2 proteins was performed on paraffin-embedded sections from 85 stage I NSCLC patients who underwent surgery and were followed up for 32 to 44 (median, 39.0; mean, 37.1) months postoperatively. Differences in survival rates were evaluated by log rank test. The prevalence of p53, HER-2/neu, and bcl-2 expression in stage I NSCLC is 59%, 29%, and 46%, respectively. HER-2/neu expression is seen more frequently in adenocarcinomas, and bcl-2 is seen more frequently in squamous carcinomas. p53 and HER-2/neu expression in stage I NSCLC is associated with significantly short survival. Patients whose tumors were both p53 and HER-2/neu positive had the worst outcome, with a survival rate of only 20%, compared with 80% in those whose tumors were both p53 and HER-2/neu negative (P =.0003). The survival rates were 54% in patients who were p53 positive but HER-2/neu negative and 50% in those who were in p53 negative, HER-2/neu positive. The differences among these 4 groups were statistically significant (P =.001). Bcl-2 does not seem to be a prognostic factor for survival. Multivariate analysis showed that overexpression of p53 and HER-2/neu, presence of angiolymphatic invasion, and tumor size > 3.0 cm were independent factors predicting poor survival. p53 and HER-2/neu by IHC staining appear to be valuable prognostic markers in stage I NSCLC patients after surgery. The worst outcome was seen in patients who expressed both p53 and HER-2/neu, suggesting that these patients might benefit from additional adjuvant therapy. HUM PATHOL 33:105-110. Copyright © 2002 by W.B. Saunders Company

Section snippets

Patients

Eighty-five patients with stage I NSCLC who underwent either lobectomy or pneumonectomy at Allegheny General Hospital between December 1995 and January 1997 were selected in this study and followed up for 32 to 44 (median, 39.0; mean, 37.1) months postoperatively. Sections of the primary tumor from each case were fixed in 10% formalin and embedded in paraffin. The diagnosis of NSCLC and categorization of cell type were based on conventional morphologic criteria,31 and the histopathologic stage

Results

Figure 1 shows the staining of p53, HER-2/neu, and bcl-2 in tumors resected from stage I NSCLC using immunohistochemical methods.

. Immunohistochemical staining of p53, HER-2/neu, and bcl-2 in stage I NSCLC. (A) Positive staining for p53 in the nuclei of tumor cells. (B) Positive membranous staining of HER-2/neu. (C) Positive staining for Bcl-2 in the cytoplasm of tumor cells.

The dark brown color denotes positive staining. p53 protein is located in the nuclei of tumor cells, HER-2/neu protein is

Discussion

The key finding of the current study is that expression of p53 or HER-2/neu in stage I NSCLC is associated with poor prognosis, as are the presence of angiolymphatic invasion and tumor size > 3 cm. Patients whose tumors are positive for both p53 and HER-2/neu apparently have a worse outcome, and the worst outcome is seen in patients with more than 3 risk factors. bcl-2 does not seem to be a prognostic factor for overall survival, although it is seen more frequently in the squamous carcinomas.

References (34)

  • TM Greatens et al.

    Do molecular markers predict survival in non-small cell lung cancer?

    Am J Respir Crit Care Med

    (1998)
  • M Ebina et al.

    Relation of p53 overexpression and up regulation of proliferating cell nuclear antigen with the clinical course of non-small cell lung cancer

    Cancer Res

    (1996)
  • DJ Slamon et al.

    Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene

    Science

    (1987)
  • C Wright et al.

    Expression of c-erbB-2 oncoprotein: A prognostic indicator in human breast cancer

    Cancer Res

    (1989)
  • DC Allred et al.

    HER-2/neu in node-negative breast cancer: Prognostic significance of overexpression influenced by the presence of in situ carcinoma

    J Clin Oncol

    (1992)
  • BA Gusterson et al.

    Prognostic importance of c-erbB-2 expression in breast cancer

    J Clin Oncol

    (1992)
  • HB Muss et al.

    C-erbB-2 expression and response to adjuvant therapy in women with node positive early breast cancer

    N Engl J Med

    (1994)
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    *

    Address correspondence and reprint requests to Jan F. Silverman, MD, Departments of Pathology and Laboratory Medicine, Allegheny General Hospital, 320 East North Ave, Pittsburgh, PA 15212.

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