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Eur J Cardiothorac Surg 2003;23:221-228
© 2003 Elsevier Science NL

Prognostic prediction of the immunohistochemical expression of p53 and p16 in resected non-small cell lung cancer

^a Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
^b Graduate Institution of Medical Science, National Defense Medical Center, Taipei, Taiwan, ROC
^c Molecular Biology Laboratory, Department of Pathology, Tzu-Chi General Hospital, Hualien, Taiwan, ROC
^d Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC
^e Department of Mathematics, Tamkang University, Tamsui, Taipei, Taiwan, ROC
^f Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC

Received 8 July 2002; received in revised form 25 October 2002; accepted 5 November 2002.

* Corresponding author. Tel.: +886-2-87927190; fax: +886-2-23644697
e-mail: cpyupath{at}ndmctsgh.edu.tw

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Objective: p53 and p16(INK4) are the common and important tumor suppressor genes. Aberrant expression of p53 or p16 protein has been reported in various malignancies including lung cancer. Our aim was to investigate the association of p53 and p16 expression in resected non-small cell lung carcinoma (NSCLC) and evaluated their correlation with clinocopathologic features and survival. Methods: p16 and p53 expression were detected by immunohistochemical analysis of 90 paraffin specimens of resected NSCLC, including 35 squamous cell carcinoma, 47 adenocarcinoma, and eight large cell carcinoma, between stages I and IV. The immunohistochemical study was performed using the labeled streptavidine–biotin method with anti-p53 and anti-p16 monoclonal antibodies. Results: Fifty-two (57.8%) and 36 (40%) of 90 patients revealed aberrant immunostaining for p53 (p53+) and p16 (p16+), respectively. While 19 cases (21.1%) showed abnormal immunoreactivity for both p16 and p53. (p53+/p16+). There was no correlation of p53 or p16 expression with the clinicopathologic features. The Kaplan–Meier survival analysis demonstrated that patients with p16+, p53+, late stages, and nodal or distal metastasis had poor survival status (P=0.006, 0.013, <0.001, <0.001 and 0.018, respectively). Further analysis demonstrated that p53 status was a significant prognostic factor in stage I NSCLCs (P<0.001), and p16 status in stage I and II NSCLCs (P<0.001, P=0.003, respectively). Furthermore, patients whose tumors were both p53 and p16 aberrant expression had worse outcome compared with those whose tumors were both normal expression of p53 and p16 (5-year survival rate: 5 vs. 76%, P<0.001). In Cox's regression model, the aberrant expression of p16, p53, advanced stages and combined aberrant expression of p53/p16 survived for a significant shorter period. Conclusions: The results indicated that aberrant expression of p16 and p53 are significant and independent, predictable prognostic factors for resected NSCLC, especially in early stage of NSCLCs. The worst prognosis was seen in patients whose tumors had both aberrant expression of p53 and p16. Further prospective trials may be aimed at confirming and validating these results.

Key Words: Non-small cell lung cancer • p16 • p53 • Immonohistochemical analysis • Prognosis

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
Lung cancer is one of the leading causes of cancer death in the world. The non-small cell lung carcinoma (NSCLC) accounts for approximately 75–85% of the lung cancer. NSCLC exhibits a variable clinical phenotype, even in those patients with apparently localized stages who undergo curatively surgical resection [1,2]. Despite working for the improvements in early detection, intensive therapeutic efforts for NSCLC in past two decades, certain patients are wrecked by rapid disease recurrences and progression, and no real improvement in the survival of lung cancer is achieved. To date, the tumor stages as summarized in the tumor node metastasis (TNM)-system is the most significant prognostic parameter, other additional predictors are required for considering adjuvant therapy to improve the survival. Numerous studies suggest that a variety of biologic markers predict survival in NSCLC patients who have undergone surgery [1,3–5], even though it might be complex and controversial [6,7]. Assuming that the putative biological markers are independent variables, multiple markers might be more informative than any single marker [4,8,9]. The phenomenon of tumor cell heterogeneity for different biologic markers has gained increased interest because of important implications for clinical behavior such as metastasizing properties, therapy response and post-operative survival [10,11]. Even so, incompatible results were reported in the literature, and further investigations for their interactive effect and correlation will be required.

The p53 tumor-suppressor gene, involved in cell cycle regulation, has anti-proliferative and anti-transforming activity [12,13]. p53 gene could induce cell arrest in Gl phase and apoptosis [14]. p16, the gene product of CDKN2A/p16NK4d, binds CDK4 and inhibits the formation of CDK4/cyclin D complexes, resulting in the inhibition of the cell cycle-dependent phosphorylation of the Rb protein [15]. The loss of cell cycle regulatory function of the p53 and p16 was implicated in the development and progression of cancers [13,16]. We demonstrated aberrant p53 and p16 expression in patients with NSCLC who received surgical resection by using immunohistochemical techniques. We analyzed the association between the expression of p53 and p16, alone or combined, and their correlation with the clinicopathologic features and survival of these patients for prediction of prognosis and consideration of post-operative adjuvant therapy.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
2.1. Patients and tumor specimens
A total of 90 formalin-fixed and paraffin embedded specimens of normal and NSCLC were obtained from the archives of the Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan between 1985 and 2000. These were serial patients chosen only because of surgical resection of tumor, the availability of sufficient follow-up data and interpretable immunostaining results. All patients underwent surgical resection (lobectomy or pneumonectomy) and complete mediastinal lymph nodes dissection in our department. Histologically, the diagnoses and classifications of these tumors were based on conventional morphologic criteria [17]. The post-operative pathologic stage was determined according to the TNM staging system of the American Joint Committee on Cancer [2]. Surgical stage was recorded by the results of primary tumor features and sampling of mediastinal lymph nodes at the time of resection. Patients were followed-up at every 3 months in the first postoperative year, at 6 months interval during the second and third year, and once a year thereafter. Follow-up evaluations consisted of physical examination, biochemical profile, chest radiograph, computed tomography (CT) scan of brain and chest, abdominal ultrasound and technetium bone scan. Data on recurrences and cause of death were obtained for all patients.

2.2. Immunohistochemical staining
A pathologist before immunostaining reviewed hematoxylin and eosin-stained slides in each case to confirm the primitive diagnoses. Consecutive 4 µm-thick sections were cut from each trimmed paraffin block, and mounted on gelatin-dichromate-coated glass slides (Dako). The expression of various oncoproteins of the tumor cells were determined by immunohistochemical staining of histological sections using specific monoclonal antibodies as previously described [18]. In brief, following deparaffinization, hydration and a blocking step with 0.1% H₂O₂ in phosphate buffered saline (PBS), formalin-fixed paraffin-embedded sections were pretreated with 0.05% saponinin for 30 min at room temperature. PBS, the sample was boiled for 10 min in 10 mM sodium citrate, pH 7.0 and subsequently incubated for 20 min at room temperature with 10% goat serum in PBS to suppress non-specific binding of the primary antibody. The slides were incubated at room temperature with monoclonal antibodies against p53 protein (DO-7; Dako SA, Glostrup, Denmark; 1:50 in dilution) and p16 protein (F12; Santa Cruz Biotechnology, California, USA, 1:50 in dilution). The samples were then incubated with biotinylated secondary antibody at 15 µg/ml (Oncogene Science Inc., Uniondale, New York, NY, USA). After incubation in an avidin-biotinylated horseradish peroxidase solution, the samples were exposed to DAB solution for 6 min and subsequently counterstained with hematoxylin.

2.3. Staining interpretation
All stained slides were evaluated using standard light microscope and interpreted by two experienced pathologists. Cancerous epithelium was examined for the presence of p16 and p53 immunostaining. An index of either protein expression was calculated as the number of positive cells out of total cancer cells. A positive immunostaining for p53 was defined as nuclear reactivity of neoplastic cells to the p53 antibody. p16 immunoreactivity disregarded cytoplasmic staining as non-specific reactivity for p16 antibody. These staining patterns and cellular locations agree with previous reports [9,19,20]. We simply divided the tumor cells to negative and positive reactivity for p53 and p16. For p16 immunostaining, the most positive staining specimen showed diffuse nuclear staining and only a few samples showed 10–50% positive stained nuclei. If the proportion of stained cells was <10% of all in the tumor, and the admixed non-neoplastic tissue showed positive nuclear staining, it was considered to be negative for p16 immunoreactivity (aberrant p16 expression, p16+). If the positive stained nuclei was >10% of all nuclei in the tumor, it was considered to be positive (not aberrant, or normal p16 expression, p16-). If there was no nuclear reactivity in the non-neoplastic tissue, the samples were considered to be uninterruptible. For p53 immunostaining, all the stained nuclei pattern a value of >10% staining of total tumor cells that was used as a cut-off to define positive staining (aberrant p53 expression, p53+), and the others were judged as negative (normal p53 expression, p53-).

2.4. Statistical analysis
The results of immunoreactivity of p16 and p53 were correlated with clinicopathologic variables (age, sex, tumor location, histologic type, TNM status, stage of the tumor) by using chi-square test or Fisher's exact test. The survival curves were analyzed by means of Kaplan–Meier method, and their difference by the log–rank test. Multivariate analysis for survival was performed using the Cox proportional hazards models. The SPSS 10.0 statistical software package (SPSS, Inc., Chicago, IL, USA) was employed for all analysis. The criterion for significance level was considered at P<0.05.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

 
3.1. Clinicopathologic features
The patients consisted of 69 men and 21 women, and their mean age at surgery was 62.8 years (range, 24–83 years). Forty-seven tumors were classified as adenocarcinomas of lung (including 18 bronchioalveolar carcinomas), 35 as squamous cell carcinomas, and eight as undifferentiated large cell carcinomas. Thirty-six were in stage I (IA: 16; IB: 20), 26 in stage II (IIA: 18; IIB: eight), 22 in stage III (IIIA: 20; IIIB: two), and six in stage IV. The patients had been followed up through a period from 1 to 121 months (median follow-up period: 48.3 months). The clinicopathologic features of the patients included in the study were summarized in Table 1.

A correlation analysis was performed with the clinicopathologic parameters including age, gender, tumor location, histopathologic classification of the tumors, and pathologic TNM parameters and stages. There was no significant correlation between p53 or p16 expression and clinicopathologic factors (Table 1).

The relationship between the clinicopathologic parameters or immunoreactivity of p53, p16 and post-surgical survival status was analyzed and summarized in Table 2. According to our univariate survival analysis (the Kaplan–Meier survival curves), the pathologic staging, nodal involvement, distal metastasis, and p53, p16 immunhistochemical expression exhibited statistically positive significance in survival (P<0.001, <0.001, 0.018, 0.013, 0.006) (Figs. 1A and 2A ). The influence of p53 or p16 expression on patients' survival in different pathologic stages of NSCLC had also been analyzed. The results showed that the expression of p53 was a significant prognostic factor in stage I, but not in stage II or III NSCLC patients (P<0.001, P=0.42, P=0.65, respectively; Fig. 1B–D). Otherwise, the expression of p16 protein was a significant prognostic factor in stage I and II patients, but not in stage III patients (P<0.001, P=003, P=0.13, respectively; Fig. 2B–D). To further evaluate the combined immunohistochemical analysis of p53 and p16 expression, we divided the NSCLC patients into different prognostic groups depending on p53 and p16 features (p53+/p16+, p53+/p16-, p53-/p16+, p53-/p16-). It revealed that patients' tumor cells with concurrent aberrant immunoreactivity of p53 and p16 (p53+/p16+) survived for the shortest time period when compared to other groups (5-year survival rates, 76, 55, 35, and 5% in patients with p53-/p16-, p53-/p16+, p53+/p16-, p53+/p16+, respectively, P<0.001) (Fig. 3 ). The prognostic importance of these factors in the univariate analysis was surveyed with Cox's proportional hazards modeling (Table 3). For all patients, altered p53, p16 expression and later staging were significant in the multivariate analysis (P=0.022, 0.033 and 0.029, respectively). The combination of p53 and p16 aberrant expression was independent marker of poor prognosis for resected NSCLC patients (P=0.011).

View larger version (23K): [in this window] [in a new window]   Fig. 1. Kaplan–Meier's survival curves according to tumor staging, immunoreactivity for p53 protein of patients with NSCLC who underwent surgical resection. Statistical analyses were reached by log–rank test. (A) Overall survival of 90 patients with NSCLCs after operation according to their tumor p53 expression (P=0.013). (B) Survival curves of 36 patients with stage I NSCLCs after operation according to their tumor p53 expression (P<0.001). (C) Survival curves of 26 patients with stage II NSCLCs after operation according to their tumor p53 expression (P=0.42). (D) Survival curves of 22 patients with stage III NSCLCs after operation according to their tumor p53 expression (P=0.65).

View larger version (23K): [in this window] [in a new window]   Fig. 2. Kaplan–Meier's survival curves according to tumor staging, immunoreactivity for p16 protein of patients with NSCLC who underwent surgical resection. Statistical analyses were reached by log–rank test. (A) Overall survival of 90 patients with NSCLCs after operation according to their tumor p16 expression (P=0.006). (B) Survival curves of 36 patients with stage I NSCLCs after operation according to their tumor p16 expression (P<0.001). (C) Survival curves of 26 patients with stage II NSCLCs after operation according to their tumor p16 expression (P=0.003). (D) Survival curves of 22 patients with stage III NSCLCs after operation according to their tumor p153 expression (P=0.13).

View larger version (21K): [in this window] [in a new window]   Fig. 3. Survival curves of all patients classified according to the presence or absence of p53 and p16 expression, showing a significant worse survival in the concurrent aberrant expression of p53 and p16 (p53+/p16+) than others (P<0.001).

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion References

p53, a nuclear phosphoprotein, is considered as the ‘guardian of the genome’ and plays a role in regulating cell cycle progression at the G1/S transition. p53 protein, with a very short half-life, normally, is not detected in the normal lung tissue. Mutations of p53 gene result in increased stability of its product and accumulate in the cells to detectable levels by immunohistochemical methods [21]. While the importance of p53 mutations in the carcinogenesis of human cancer, including lung cancer, is obvious, it is still not clear whether p53 alternations affect patient's survival. Most of the studies have focused on the potential prognosis value of p53 expression. Some of these reports demonstrate that p53 immunostaining activity indicate a poor prognosis [8,22], while others show the contrary [9,23]. Due to the conflicting data, several studies estimated the interaction effects of p53 and other delicate clinic pathologic features or other common biomarkers, including bcl-2, Rb, p21, cycling D1, and Her-2/neu and others [3,4,8,9,24], but different results were still reported, and further investigations will be required. p53 mutation is known to occur in about one-half (34–82%) of NSCLCs. In our data, the tumors of about 58% of our patients had aberrant expression for p53, and a favorable prognosis was in normal p53 expression, significantly in stage I NSCLC patients.

The p16(INK4A) belongs to the G1 control gene involving the ‘Rb pathway’, and is also believed to be a tumor suppressor gene, and inactivation of p16 gene has been detected in various human malignancies. Several studies have reported that the aberrant p16 expression occurred in about 27–54% of NSCLCs, but its prognostic significance in NSCLC remains controversial [24,25]. In the study of Huang et al [19], a more accurate and useful genetic classification of NSCLC was performed and the alternation of p16 was considered as a significant factor for poor prognosis in squamous cell carcinoma. In our patients, 36% tumors had aberrant p16 expression, and it was a significant worse prognostic factor for resected NSCLC, but there was no correlation with the clinicopathologic factors.

The biological alternations between p53 and p16 were not analyzed individually in the previous study. Interestingly, in the current study, the concurrent alternation of p53 and p16 in resected NSCLC is associated with significantly shorter survival, compared with normal expression of both p53 and p16, in univariate or multivariate statistical analysis. But their expression does not correlate with clinicopathologic factors and other significant survival factors, such as pathologic stage, nodal involvement and distant metastasis. So p53 and p16 expression detected by immunohistochemical staining could be considered as an independent factor predicting survival in patients with resected NSCLC.

In conclusion, using immunohistochemical staining of p53 and p16 as clinical biologic markers, it may be possible to predict patients, with NSCLC, with poorer or better prognosis, especially in early stage NSCLC patients. If the current findings could be confirmed in large prospective studies, then combined analysis of p53 and p16 expression may become a useful clinical tool for stratifying patients with NSCLC into more accurate prognostic groups. Furthermore, the concurrent aberrance of p53 and p16 in NSCLC patients may identify patients with worse prognosis and more aggressive additional adjuvant therapy may be of benefit for these patients.

	Footnotes

 
¹ The first three authors contributed equally to this work.

	References

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