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Annals of Surgical Oncology 8:72-79 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Vascular Endothelial Growth Factor Expression in Stage I Non-Small Cell Lung Cancer Correlates With Neoangiogenesis and a Poor Prognosis

Helen Han, MD, Jan F. Silverman, MD, Tibetha S. Santucci, RN, Robin S. Macherey, RN, Thomas A. dAmato, MD, Ming Y. Tung, MS, Robert J. Weyant, DDS and Rodney J. Landreneau, MD

From the Departments of Pathology (HH, JFS, MYT) and Cardiothoracic Surgery (TSS, RSM, RJL), Allegheny General Hospital, and School of Dentistry (RJW), University of Pittsburgh, Pittsburgh, Pennsylvania.

Correspondence: Address correspondence and reprints requests to Dr. Rodney J. Landreneau, Dept. of Cardiothoracic Surgery, Allegheny General Hospital, 320 East North Ave., Pittsburgh, PA 15212; Fax: 412-359-6873.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: Vascular endothelial growth factor (VEGF) plays an important role in tumor growth and metastasis. We investigated the prognostic significance of VEGF overexpression, intratumoral microvessel density (MVD), and angiolymphatic invasion in stage Ia-b non-small cell lung cancer (NSCLC).

METHODS: Eighty-five patients undergoing complete surgical resection of pathologic stage Ia-b NSCLC were evaluated. The mean and median clinical follow-up were 37.1 and 39.0 months (range, 30–44 months), respectively. Paraffin-embedded tumor specimens were stained with VEGF and CD31 (a specific endothelial marker) using immunohistochemical methods. VEGF staining was evaluated, by combining both percentage of positive tumor cells and staining intensity, as low (negative and < 20% of tumor cells showing weak positivity), or high (>20% of tumor cells showing strong positivity). CD31 staining was expressed as MVD per high power field at 400x magnification. Angiolymphatic invasion was expressed as either presence or absence.

RESULTS: Low VEGF expression was seen in 25 (29%) patients, and high VEGF expression was seen in 60 (71%) patients. The survival rate in patients with low VEGF expression was significantly higher (80%) than that in those with high VEGF expression (48%, P = .018). The mean MVD in the low VEGF group was 23.7 ± 5.7 vs. 34.4 ± 9.3 in the high VEGF group (P = .001). Patients with high MVD also had a significantly lower survival rate than did those with low MVD count (46% vs. 73%, P = .0053). Age, sex, tumor type, and tumor differentiation were not found to be associated with overall survival. The presence of angiolymphatic invasion and T2 stage (i.e., tumor size > 3 cm) were associated with decreased survival. High VEGF expression, tumor size, and angiolymphatic invasion emerged as three independent factors predicting worsening prognosis using multivariate analysis.

CONCLUSION: High VEGF expression within stage I NSCLC is closely associated with high intratumoral angiogenesis and poor prognosis. Immunohistochemical evaluation of T stage and VEGF expression along with examination of angiolymphatic invasion perioperatively may aid in predicting prognosis. Adjuvant therapies aimed at retarding tumor angiogenesis may be considered for stage I NSCLC patients with high VEGF levels.

Key Words: Vascular endothelial growth factor (VEGF)— • Microvessel density— • CD31— • Angiolymphatic invasion— • Non-small cell lung cancer.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Lung cancer is the leading cause of cancer deaths in both men and women worldwide. Histopathologically, the majority of lung cancer (80%) is classified as non-small cell carcinoma (NSCLC), of which there are three major subtypes: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. The survival rate for NSCLC has remained stable over the last several decades, suggesting that there has been little progress in treatment.1,2 Although surgery remains the treatment for localized tumors, patients with the same stage of disease can show marked differences in survival, as demonstrated by the wide range of 5-year survival rates reported for stage I NSCLC—50% to 80%.2–5 In addition, the nodal status is not relevant in stage I NSCLC. Clearly, additional tumor markers or identification of histopathological features is needed to better assess the survival probability and aid in identifying additional treatment modalities in stage I disease.

Vascular proliferation or tumor angiogenesis is a requirement for solid tumor growth and is regulated by angiogenic factors produced by tumor cells.6–8 Although the factors causing tumor angiogenesis are not completely understood, the current leading candidates include vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF).9,10 VEGF, also known as vascular permeability factor, is a soluble dimeric 34- to 42-kDa protein with potent angiogenic, mitogenic, and vascular permeability-enhancing activities specific for endothelial cells.11,12 VEGF expression has been detected in some malignant tumors, including ovarian cancer,13 melanoma,14,15 gastric carcinoma,16,17 pancreatic adenocarcinoma,18 breast cancer,19 and lung cancer.20

Using immunohistochemical techniques and multivariate analyses we investigated (1) the prognostic value of VEGF expression in stage I NSCLC; (2) correlation of VEGF expression with microvessel density (MVD), which closely reflects the intratumoral angiogenesis; and (3) the prognostic importance of the relationship between VEGF expression and the clinical pathological features of stage I NSCLC.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
This retrospective study included 85 patients with NSCLC who underwent either lobectomy or pneumonectomy at Allegheny General Hospital between December, 1995, and January, 1997. All patients underwent preoperative mediastinoscopy or mediastinal exploration during surgery as part of the staging. None of the patients received pre- or postsurgical radio-or chemotherapy. Ten patients underwent pneumonectomy, and 75 patients had lobectomy. Sections of the primary tumor from each patient were fixed in 10% formalin and embedded in paraffin. The diagnosis of NSCLC and categorization as to cell type were based on conventional morphological criteria.21 Histopathological stage of each tumor was determined postoperatively according to the tumor-node-metastasis (TNM) classification system.22 Survival was assessed from review of medical charts and computerized databases.

Immunohistochemical Staining
Consecutive 5-µm sections were cut from each paraffin-embedded study block and were stained for VEGF and CD31 using the immunoperoxidase technique. Appropriate positive and negative controls were included with each set of stains. The primary antibodies used were a rabbit polyclonal antibody (Santa Cruz Biotechnology, Santa Cruz, CA) at a 1:500 dilution for VEGF and a mouse monoclonal antibody (Ventana, Tucson, AZ) for CD31. The slides were first baked at 60°C to 62°C and then rehydrated in xylene and graded in ethanol. Antigen retrieval for VEGF was performed by microwaving the slides in 10 mM of citrate buffer, pH 6.0 for 10 minutes. Slides for CD31 stain were pretreated by protease for 8 minutes. They were further processed by the addition of primary antibodies and rinses, horseradish peroxidase-conjugated secondary antibody and rinses, and color development with diaminobenzidine tetrahydrochloride.

Evaluating VEGF Expression, Intratumoral Microvessel Density, and Localized Angiolymphatic Invasion
Expression of VEGF and vessel count were evaluated by two investigators without knowledge of patient outcome. VEGF staining was scored by combining both the percentage of positive tumor cells and the staining intensity, defined as low (< 20% of tumor cells showing weak positivity) or high (more than 20% of tumor cells showing moderate or strong positivity). The 20% cutpoint was chosen for two reasons: (1) when we categorized the patients according to the percentage of tumor staining cells into the 0–20%, 21–50%, and >50% groups, there was no significant difference in survival between the 21–50% and > 50% groups; and (2) nonspecific staining could contribute to the weak positivity or relatively small number of positively stained cells (i.e., <20%). In addition, this number (20%) has been used in the literature as the cutpoint for defining other immunohistochemical staining. Paratumoral lung tissues from the same patients were always stained with low intensity due to the absence of tumor cells; therefore, a high staining intensity also was defined as overexpression of VEGF. CD31 was expressed as microvessel density (MVD) by light microscopy in areas of the tumor containing the highest numbers of capillaries and small venules. The highly vascular areas were identified by scanning tumor sections at low power. After the area of highest neovascularization was identified, a vessel count was performed on a 400x field (40x objective and 10x ocular; area 0.18 mm3). The presence of vessel lumens was not necessary for a structure to be defined as a vessel.23 Angiolymphatic invasion was assessed by examining the direct invasion of tumor cells within the angiolymphatic vessel spaces and thus was defined as either presence or absence. No effort was made to differentiate intratumoral and peritumoral angiolymphatic invasions.

Statistical Analysis
The log-rank test was used to determine statistical differences in overall survival, which is defined as the time between surgery and death, and the various individual potential prognostic factors including age, sex, T stage, histological type, differentiation, angiolymphatic invasion, VEGF expression, and MVD. Survival curves were obtained using the Kaplan-Meier method. Multivariate analyses were performed using the Cox regression model to identify independent prognostic factors. The Student t-test and {chi}2 test were used to evaluate the differences of mean and of the percentages of VEGF expressions.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Follow-Up and Survival by Main Clinical Features
The 85 patients consisted of 51 men (60%) and 34 women (40%), with a mean age of 69.3 years (range, 42 to 84 years). The mean and median follow-up times were 37.1 and 39.0 months (range, 30 to 44 months), respectively, with a survival rate of 58%. Ten patients underwent pneumonectomy, and 75 patients had lobectomy. The univariate analysis of the overall survival in relation to the demographic and histopathologic features of all 85 patients is presented in Table 1. Of all factors tested, T stage and angiolymphatic invasion were found to be associated with a significant decrease in overall survival ( Figs. 1 and 2). Gender, age, histology type, and tumor differentiation were not significantly associated with prognosis, although the survival of 58 patients with poorly differentiated disease tended to be lower (Table 1). There was no significant difference in survival between the pneumonectomy and lobectomy groups, although the number of patients may have been too small to allow meaningful detection.


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  		Table 1. Univariate analysis of clinicopathological factors in relation to overall survival
 


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  		FIG. 1. Survival of 85 patients with stage I NSCLC as a function of tumor size.

 


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  		FIG. 2. Survival of 85 patients with stage I NSCLC as a function of absence (dashed line) or presence (solid line) of angiolymphatic invasion.

 
Relationships Among VEGF Expression, Intratumoral Neoangiogenesis, and Patient Survival
The VEGF expressions and intratumoral neoangiogenesis represented by MVD are shown in Table 2 and Figs. 3 through 5. Low VEGF expression was seen in 25 (29%) patients. High VEGF expression was seen in 60 (71%) patients. The overall survival rates were 80% and 48% for patients with low and high VEGF expressions, respectively (P = .018; Fig. 4). Evaluation of the association between VEGF expression and neoangiogenesis showed that patients with low VEGF expression had a mean MVD of 23.7 ± 5.7, as opposed to 34.4 ± 9.3 for patients with high VEGF expression (P = .001), suggesting that high VEGF expression was closely associated with increased intratumoral angiogenesis (Table 2). Compared with patients whose MVD count was lower than 30, high MVD patients (defined as >=30 microvessels per high-power field) also had a lower survival rate (73% vs. 46%, P = .0053; Table 2, Fig. 5).


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  		Table 2. Effects of VEGF expression and MVD on overall survival
 


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  		FIG. 3. VEGF expression and CD31 staining by immunohistochemical method in NSCLC. (A) High (strong positive) VEGF. (B) Low (negative) VEGF. (C) Tumor area with high microvessel density by CD31 staining. (D) Tumor area with low microvessel density by CD31 staining.

 


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  		FIG. 4. Survival of patients with stage I NSCLC as a function of high and low VEGF expression.

 


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  		FIG. 5. Survival of 85 patients with stage I NSCLC as a function of high (>30) and low (<=30) MVD.

 
Relationship Between VEGF Expression and Clinicopathologic Features
The relationship between VEGF expression and the clinicopathologic features of stage I NSCL is noted in Table 3. High VEGF expression was identified in 60 of the total 85 tumors (71% ), and was more common in patients 65 years of age or younger who had adenocarcinomas or large cell carcinomas that were moderately and poorly differentiated, although these findings were not statistically significant. The incidence of high VEGF expression remained relatively stable in T1 and T2 tumors. The incidence of low VEGF expression also showed little change in T1 and T2 tumors. High VEGF expression was evenly distributed in male and female patients having tumors with and without vascular invasion.


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  		Table 3. Correlation between VEGF expression and clinicopathologic features
 
Detailed analyses of VEGF expression and patient survival with regard to each individual histopathological characteristic also are shown in Table 3. High VEGF expressions usually were associated with lower survival rates, except in squamous cell and adenosquamous carcinomas. In squamous cell carcinoma the high VEGF tumor group showed a trend toward decreased survival when compared to patients in the low VEGF group (57% vs. 64%), although this was statistically insignificant (P = .55, not shown). In adenosquamous carcinoma the number of cases was too small (n = 3) to allow any meaningful analysis of differences between the two groups. In patients identified as having either high or low VEGF expression, the survival rates were not significantly different between T1 and T2 stages, male and female, age <=65 and >65 years old, and histologic tumor types and tumor differentiation.

The 17 patients whose tumors exhibited low VEGF and negative vascular invasion had a survival rate of 88%, whereas the 22 patients whose tumors exhibited high VEGF and positive vascular invasion had the worst outcome, with a survival rate of only 18% (P = .0001, not shown). The survival rates were 63% in patients with positive vascular invasion only, and 60% in patients with high VEGF only. Therefore, vascular invasion was associated with decreased survival in patients with high VEGF expression (P = .004). However, vascular invasion in patients with low VEGF expression was not associated with a significant decrease in survival (P = .37).

Multivariate Analysis
To determine which of the factors were important predictors of lung cancer-related death, a multivariate analysis using the Cox proportional hazards model was performed. Tumor size greater than 3 cm, angiolymphatic invasion, and VEGF overexpression emerged as independent prognostic factors ( Table 4). Fifteen of 16 patients (94%) with all three factors and 1 of 12 patients (8%) with none of these factors died during the study period. Nine of 26 patients (35%) with one factor and 11 of 31 patients (35%) with two factors died in the same period. The survival curve generated by the Kaplan-Meier method is shown in Fig. 6.


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  		Table 4. Multivariate analysis of pathological factors and molecular markers
 


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  		FIG. 6. Survival of patients with stage I NSCLC as a function of 0 to 3 independent factors derived by the multivariate analysis.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The VEGF gene is normally expressed in nonmalignant human tissues including lung, kidney, adrenal gland, liver, and stomach.24 However, the circulating serum VEGF level usually is lower in healthy individuals than in patients with either lung cancers or benign pulmonary diseases and does not seem to correlate with tumor burden.25 By binding to specific tyrosine kinase receptors found on endothelial cells, VEGF acts as a potent angiogenic factor for neovascularization.11,26 Because tumor growth and metastasis depend primarily on angiogenesis,6,8 the relationships between VEGF expression and the clinical outcomes of a several solid tumors have been studied.15–19 An association between VEGF overexpression and relapse-free or overall survival, with significantly shorter survival times, was found in patients with VEGF-rich breast cancer.19,27 VEGF overexpression also was reported as a significant prognostic factor for invasive gastric carcinoma17 and possibly was correlated with disease recurrence.16 However, VEGF overexpression was found not to be a predictor of survival or recurrence for patients with resectable pancreatic adenocarcinoma,18 nor was it a useful prognostic indicator for malignant melanoma.15

Our study found a significantly decreased overall survival rate in patients with stage I NSCLC who demonstrated immunohistochemical overexpression of VEGF (48% vs. 80%). This result supports a recent report that demonstrated that VEGF overexpression was associated with a higher risk for recurrence for stage I NSCLC28 and is in agreement with those published for breast and gastric carcinomas.17,19,27 VEGF overexpression seems to be more common in patients younger than 65 years and having moderately and poorly differentiated adenocarcinoma or large cell carcinoma. Decreased survival rate was most significant for adenocarcinoma. No statistically significant association of VEGF in squamous cell carcinoma was seen (Table 3). This finding could be due to either inadequate number of cases or less advanced pathological stage squamous cell carcinoma analyzed, because when all stages (I-III) of squamous cell carcinoma were analyzed, overexpression of VEGF also was associated with a poorer prognosis.29

The current study also demonstrated that overexpression of VEGF was associated with increased neovascularization (MVD) as assessed by staining of CD31 (Table 2) in stage I NSCLC. Neovascularization was found to correlate with the incidence of metastasis in NSCLC30 and with relapse after surgery in adenocarcinoma.31 The decreased survival rate found in the high MVD group in our current study supports the previous observations made in NSCLC. However, this high MVD-associated poor survival probably is not an independent prognostic factor, because high MVD may result from high VEGF expression. Multivariate analysis based on the current data (Table 4) supports the notion that overexpression of VEGF, but not MVD (CD31, P = .398), is an independent factor predicting a poor outcome for stage I NSCLC. However, whether angiogenesis can accurately predict metastasis is still uncertain.32,33

Another strong independent factor that has emerged from analysis of the current data is the presence or absence of angiolymphatic invasion in the resected tumor (Table 4). This invasion can be viewed as a marker for minimal disease in other lymphatic channels after resection. In tumors without VEGF overexpression, the presence of angiolymphatic invasion decreased the survival rate from 88% to 63%, although this was not statistically significant. Angiolymphatic invasion dramatically decreased the survival rate in patients who overexpressed VEGF (from 60% to 18%). The most striking difference in survival was observed between patients who had neither VEGF overexpression nor angiolymphatic invasion and those who had both (88% vs. 18%). Thus, there seems to be a synergistic effect between VEGF overexpression and angiolymphatic invasion in stage I NSCLC. Because VEGF is produced primarily by the tumor cells, and the site of action for VEGF is primarily the endothelial cells of the microvessels, it is possible that invasion of tumor cells into the microvessels creates a favorable microenvironment for VEGF action (e.g., close contact with its receptors) and by doing so significantly stimulates neovascularization and cancer growth, in addition to increasing the possibility of distant hematogenous metastasis.

Tumor size was found to be a significant factor in both univariate and multivariate analyses in our current study. Analysis reveals that the magnitude of survival decrease remained similar in both low and high VEGF expression groups (Table 3). These data appear to agree with many previous studies that generally showed a worsening outcome with increased T stage.2,28 Tumor size, however, is a variable dependent on its growth rate. A slowly growing tumor takes much longer to reach 3 cm in size than a fast-growing one. In other words, the overall worsening prognosis associated with T2 stage may be a reflection that some T2 tumors are intrinsically fast-growing. Thus, the characteristics that govern the growth rate of the tumor rather than its mere size may be more important and accurate in predicting the worsening outcome.

Although VEGF overexpression has an effect on neoangiogenesis and tumor growth stimulation, the frequency of VEGF overexpression in T2 tumor is not significantly higher than in T1 tumor, indicating that VEGF overexpression remains stable when tumor advances from T1 to T2 (Table 3). Similarly, the percentage of low VEGF expression also remains stable in T1 and T2 tumors. A significant decrease in survival rates is seen in both T1 and T2 patients who overexpressed VEGF. Furthermore, the survival rate in patients with T2 tumor and low VEGF expression actually is higher than that for those with T1 stage and high VEGF expression (69% vs. 56%, Table 3). All these results suggest that VEGF overexpression is an independent variable in stage I NSCLC patients.

In conclusion, we believe that high VEGF expression within stage I NSCLC is closely associated with high intratumoral angiogenesis and poor prognosis. VEGF overexpression, angiolymphatic invasion, and tumor size greater than 3 cm are independent risk factor predicting a poor prognosis for NSCLC. The highest mortality is seen in stage I patients with all three factors (94%). Immunohistochemical evaluation of VEGF expression along with examination of angiolymphatic invasion perioperatively has value in predicting prognosis. Adjuvant therapies aimed at retarding tumor angiogenesis may be considered for stage I NSCLC patients with high VEGF levels.


   Footnotes
 
Presented at the 53rd Annual Meeting of the Society of Surgical Oncology, New Orleans, Louisiana, March 16-19, 2000.

Received for publication March 17, 2000. Accepted for publication September 6, 2000.


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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
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