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J Thorac Cardiovasc Surg 1998;115:1007-1011
© 1998 Mosby, Inc.

GENERAL THORACIC SURGERY

Vascular endothelial growth factor expression in non-small-cell lungcancer: Prognostic significance in squamous cell carcinoma

Hideyuki Imoto, MD, Toshihiro Osaki, MD, Satoshi Taga, MD, Akira Ohgami, MD, Yuji Ichiyoshi, MD, Kosei Yasumoto, MD

From the Department of Surgery II, School of Medicine,University of Occupational and Environmental Health, Kitakyushu, Japan.

Received for publication March 25, 1997. Revisions requested June 12, 1997. Revisions received Nov. 11, 1997. Accepted for publication Nov. 11, 1997. Address for reprints: Hideyuki Imoto, MD, Department of Surgery II,School of Medicine, University of Occupational and Environmental Health, 1-1Iseigaoka, Yahatanishi-ku, Kitakyushu 807, Japan.


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background: Recently, some studies havefocused on the tumor angiogenesis and its prognostic value. We studied theexpression of vascular endothelial growth factor, microvessel counts, and serumconcentrations of vascular endothelial growth factor to investigate theirassociation with clinicopathologic factors and prognosis in non-small-cell lungcancer.
Methods: The expression ofvascular endothelial growth factor was determined by an immunohistochemicalanalysis from 91 paraffin specimens of completely resected non-small-cell lungcancers using anti–growth factor polyclonal antibody. Microvessel stainingwas performed by immunohistochemical analysis with anti–factor VIII–relatedantigen polyclonal antibody. Measurement of the serum concentrations of vascularendothelial growth factor used the sandwich enzyme-linked immunosorbent assaytechnique.
Results: Expression of vascularendothelial growth factor was detected in 48 of the 91 tumors. The positiveratio was significantly higher in patients with adenocarcinoma than in thosewith squamous cell carcinoma. The microvessel counts were significantly higherin the patients with nodal metastasis than in those without nodal metastasis.The serum concentrations of vascular endothelial growth factor were alsosignificantly higher in the patients with T3-4 disease than in those with T1-2disease. The microvessel counts were closely associated with expression ofvascular endothelial growth factor. The prognosis of patients with a positivegrowth factor ratio was significantly worse than that of the patients with anegative ratio (p = 0.002), especially insquamous cell carcinoma. According to a multivariate analysis, only nodal statusand expression of vascular endothelial growth factor were found to beindependent prognostic factors.
Conclusions:The expression of vascular endothelial growth factor was one of the mostimportant prognostic factors in completely resected non-small-cell lung cancer,especially in squamous cell carcinoma. (J Thorac Cardiovasc Surg1998;115:1007-14)


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
Angiogenesis is required for the growth and metastasis of solid tumors.Go Go l,2 Tumor angiogenesis is also closelyassociated with prognosisGo Go 3-6 and may be regulated byangiogenic factors, which are produced by the tumor cells.Go Go 7-10Recently, several angiogenic factors, such as fibroblast growth factor,Go 8 hepatocyte growth factor,Go 9 and platelet-derived growth factor,Go 10 have been identified. Vascularendothelial growth factor (VEGF), also known as vascular permeability factor, isone such factor that is a homodimeric 34 to 42 kDa, heparin-binding glycoproteinwith potent angiogenic, mitogenic, and vascular permeability–enhancingactivities specific for endothelial cells.Go Go 11-13 The gene for human VEGF isorganized into eight exons. As a result of alternative splicing, fourtranscripts encoding mature monomeric VEGF containing 121, 165, 189, and 206amino acid residues (VEGF121, VEGF165, VEGF189,and VEGF206) have also been detected. VEGF121 and VEGF165are diffusible proteins that are secreted into the medium. On the other hand,VEGF189 and VEGF206 have a high affinity for heparin andare mostly bound to heparin-containing proteoglycans in the extracellularmatrix.Go Go 11-13 VEGF has been identified insome malignant tumors, for example, ovarian cancer,Go 14 melanoma,Go 15 and gastric cancer.Go 16 It has also been identified inlung cancerGo 17; however,there has been no report on VEGF expression as a prognostic factor.

Recently, the postoperative prognosis has improved in non-small-cell lungcancer (NSCLC),Go 18 but thisprognosis still remains worse than for other carcinomas. In this study, weexamined the VEGF expression in tumor tissue to investigate the correlation withclinicopathologic factors and prognosis in patients with completely resectedNSCLC. In addition, we also examined the microvessel counts that closely reflectangiogenesis in tumor tissue. Thanks to recent advances in medical technology, aserum assay of VEGF concentrations can now be easily performed. We also examinedthe serum VEGF concentrations to investigate both their clinical value andcorrelation with VEGF expression.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Samples
Resected specimens from 91 consecutive patients with lung adenocarcinomaor squamous cell carcinoma who could be followed completely and who underwent acomplete surgical resection at our institution from September 1991 to March 1995were studied. The median follow-up period was 725 days. The patients ranged inage from 38 to 80 years (average, 65.6 ± 9.7 years); 69 were men and22 were women. All patients underwent diagnostic procedures before theoperation, including brain computed tomography, body computed tomography, andbone scintiscan without mediastinoscopy. The histologic types included 57adenocarcinomas and 34 squamous cell carcinomas. The pathologic stage wasclassified according to the International Staging System for Lung CancerGo 19 after a complete mediastinallymph node dissection was carried out in all cases: stage I in 32 patients,stage II in 7 patients, stage IIIA in 32 patients, and stage IIIB in 20patients. Of the 20 patients with stage IIIB disease, 18 had T4 N0-2 disease and2 had T1-3 N3 disease. A complete resection was defined as no gross andmicroscopic residual tumor remaining at the bronchial or vascular stump. Even ifmicroscopic metastasis were present in the highest mediastinal lymph node, itwas still considered a complete resection. The slides were reviewedindependently by two observers (H.I. and T.O.) who had no knowledge of thepatients' clinical data.

Immunohistochemical staining of VEGF
Formalin-fixed, paraffin-embedded tissue specimens were prepared byconventional techniques. Immunohistochemical studies were performed with thelabeled streptoavidin-biotin method with anti–VEGF rabbit polyclonalantibody A-20 (Santa Cruz Biotechnology, Santa Cruz, Calif.). This antibodyrecognizes the 121, 165, and 189 isoforms of VEGF. Five-micrometer–thicksections were dewaxed in xylene, taken through ethanol, and then incubated with0.3% hydrogen peroxide in methanol for 30 minutes to block any endogenousperoxidase activity. Then the sections were reacted with VEGF antibody (negativecontrols with nonspecific rabbit serum) in a 1:200 dilution at room temperaturefor 2 hours. The Labeled Streptavidim Biotin kit (Dako Corp., Carpintera,Calif.) provided the secondary reagents. After these treatments were completed,the diaminobenzidine method was next used to visualize peroxidase withhematoxylin as a counterstain.

The degree of polyclonal antibody reactivity with individual tissuesections was considered to be positive if unequivocal staining of the membraneor cytoplasm was seen in more than 5% of the tumor cells in the slide ofthe largest section of the tumor, as reported by Maeda and associates.Go 16

Microvessel staining and counting
Microvessels in the tumor tissue were highlighted by immunohistochemicalstaining with anti-factor VIII–related antigen polyclonal antibody A0082(Dako) in a 1:200 dilution at room temperature for 2 hours. The other method wasthe same as VEGF immunohistochemical staining. As described in another report,Go 5 any single brown-stained cells orclusters of endothelial cells that were clearly separate from the adjacentmicrovessels, tumor cells, and other connective tissue elements were consideredas a vessel. The vessels were counted in the five areas of highest vasculardensity at 200x magnification, as described in another report.Go 5 The microvessel counts wereexpressed as the mean number of vessels in these areas.

Enzyme-linked immunosorbent assay (ELISA) of serum VEGF.
After informed consent had been obtained from all patients, the serumfrom 57 of the 91 patients was stocked before the operation and frozen at–80° C. The sera were then melted at room temperature within 15minutes before being subjected to an assay. The serum VEGF assay used thequantitative sandwich ELISA technique with the VEGF ELISA kit (R&D Systems,Inc., Minneapolis, Minn.) according to the manufacturer's instructions. Twoantibodies in this assay reacted mainly to VEGF165. The opticaldensity was determined within 30 minutes after these treatments were performedwith a microtiter plate reader set to 450 nm. After averaging the duplication ofthis treatment for each sample, the concentrations of serum VEGF were calculatedwith a standard curve. The standard curve of VEGF was linear in a plot atconcentrations from 0 to 2000 pg/ml (r =0.998, p = 0.0001).

Statistical analysis
The microvessel counts and serum VEGF concentrations were expressed asthe mean ± standard deviation. The relationship between the VEGFexpression and various clinicopathologic factors were examined with the {chi}2test. The relationship between the microvessel counts, serum VEGFconcentrations, and clinicopathologic factors were examined with the unpairedStudent's t test. The relationship between themicrovessel counts and serum VEGF concentrations was examined with the Spearmanrank test. The survival curves were calculated with the Kaplan-Meier method andwere then analyzed by the log rank test. A univariate and a multivariateanalysis of various prognostic factors were assessed by the Cox'sproportional-hazards regression model.Go 20


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
The immunohistochemical detection of VEGF expression
VEGF was mainly localized in the cytoplasm of the tumor cells (Fig. 1). Tumor cells that stained strongly forVEGF were observed more often in the invasive front than in the center of thetumor, especially in squamous cell carcinoma. On the other hand, VEGF stainedrelatively homogeneously in adenocarcinoma.



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  		Fig. 1. Immunohistochemicalstaining of VEGF. A, Positive VEGFimmunostaining of squamous cell carcinoma. VEGF was mainly localized in thecytoplasm of the tumor cells (original magnification x400).B, Negative VEGF immunostaining of squamous cellcarcinoma (original magnification x400).

 
VEGF expression was detected in 48 of the 91 tumors (52.7%). TableI shows the correlation between the VEGF expression and variousclinicopathologic factors.A significant difference was noted with histologic types. The VEGF-positive ratewas significantly higher in patients with adenocarcinoma than in those withsquamous cell carcinoma (p = 0.03).However, there was no significant association between the VEGF expression andthe age at operation, sex, T stage, nodal status, or pathologic stage.


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  		Table I. Correlation between the VEGFexpression in tumor tissue and the clinicopathologic factors in 91 patients
 
Microvessel counts and serum VEGF concentrations
Table II shows the correlation between microvessel counts, serum VEGFconcentrations, and various clinicopathologic factors. Microvessel countsranged from 7 to 321 counts/200x with a mean of 85.9 ± 71.8counts/200x, and serum VEGF concentrations ranged from 0 to 2014 pg/mlwith a mean of 525  ± 442 pg/ml. Microvessel counts and serum VEGFconcentrations were not significantly associated with the histologic types. Themicrovessel counts and serum VEGF concentrations in patients with stage IIIdisease were significantly higher than in those patients with stage I-II disease(p = 0.03 and p =0.02, respectively). The microvessel counts in the tumors with nodal metastasiswere also significantly higher than in those without nodal metastasis (p = 0.04). However, the T stage was notsignificantly associated with the microvessel counts. On the other hand, theserum VEGF concentrations were significantly associated with the T stage. Theserum VEGF concentrations were significantly higher in patients with T3-4disease than in those with T1-2 disease (p =0.004) However, the nodal status was not significantly associated with the serumVEGF concentrations.


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  		Table II. Correlation between themicrovessel counts, serum VEGF concentrations, and various prognostic factors
 
Relationship between VEGF expression and microvessel counts or serumVEGF concentrations
There was a significant association between the VEGF expression and themicrovessel counts in the tumor tissue. The microvessel counts weresignificantly higher in patients with VEGF-positive tumor (102.9  ±83.3) than in patients with VEGF-negative tumor (66.8 ± 50.6) (p =0.01). On the other hand, there was no significant association between the VEGFexpression and the serum VEGF concentrations (Table III).There was no significant association between the serum VEGF concentrations andthe microvessel counts (p = 0.78).


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  		Table III. Correlation between VEGFexpression in tumor tissue, the microvessel counts, and serum VEGFconcentrations
 
Survival analysis
The prognosis of the 48 patients with VEGF-positive tumor wassignificantly worse than the 43 patients with VEGF-negative tumor (p = 0.003) (Fig. 2). Table IV shows a univariate analysis ofthe various prognostic factors.T stage, nodal status, and VEGF expression were all statistically significantfactors (p = 0.004, p =0.0001, and p = 0.003, respectively). Themicrovessel counts might appear to be a prognostic factor but not reachstatistical significant (p = 0.083);however, the serum VEGF concentrations were not an important prognostic factor (p = 0.34). A multivariate analysis with Cox'sproportional-hazards regression model was performed to investigate theindependent prognostic factors among the T stage, nodal status, VEGF expression,and microvessel counts. As a result, only the nodal status (p =0.0001) and VEGF expression (p = 0.004)were identified to be independent prognostic factors (Table V).Because the incidence of VEGF expression differed significantly between thepatients with squamous cell carcinoma and adenocarcinoma, univariate andmultivariate subset survival analysis were performed on each histologic type.Especially in the 34 patients with squamous cell carcinoma, the prognosis of thepatients with VEGF-positive tumor was significantly worse than for patients withVEGF-negative tumor (p = 0.0001) (Fig. 3). The same tendency was also observed inpatients with adenocarcinoma, but it did not reach statistical significance (p = 0.19). According to multivariate analysis oneach histologic type, VEGF expression was also an independent prognostic factorin patients with squamous cell carcinoma (p =0.03); however, it did not reach statistical significant in patients withadenocarcinoma (p = 0.24).



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  		Fig. 2. Survival curves of the91 patients according to the VEGF expression.

 

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  		Table IV. Univariate analysis of thevarious prognostic factors
 

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  		Table V. Multivariate analysis ofvarious prognostic factors
 


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  		Fig. 3. Survival curves of the34 patients with squamous cell carcinoma according to the VEGF expression.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In this study, we detected the VEGF-positive expression in 48 of 91patients (52.7%) with a completely resected stage I-III NSCLC. Weobserved no significant correlation between the VEGF expression and age, sex, Tstage, nodal status, or pathologic stage. A significant relationship was onlyseen in the VEGF expression regarding histologic types. The positive ratio ofVEGF expression in adenocarcinoma was higher than that in squamous cellcarcinoma (p = 0.03). We also found atendency that microvessel counts were higher in patients with adenocarcinomathan in those with squamous cell carcinoma. These findings mean thatadenocarcinoma has higher angiogenic potential than squamous cell carcinoma.Recently, some reportsGo Go 21,22 on genetic studies have showna difference in the incidence of certain genetic changes in histologic type oflung cancer. For example, ras mutations are found predominantly inadenocarcinoma,Go 21 whereasp53 gene mutations are more prevalent in squamous cell carcinoma than inadenocarcinoma.Go 22 Suchdifferences in the histologic type in lung cancer may be identified in bothangiogenic factors and genetic changes.

Weidner and associatesGo 23reported that the microvessel counts were closely associated with lymph nodalmetastasis in invasive breast cancer; other authors have reported them to becorrelated with systemic metastasis in NSCLC.Go Go 24,25In this study, the microvessel counts were closely associated with lymph nodalmetastasis; moreover, the microvessel counts in VEGF-positive tumors were alsosignificantly higher than in VEGF-negative tumors. It is therefore thought thatVEGF might reflect the metastatic potential through the angiogenesis of thetumor.

In this study, we also studied serum VEGF concentrations using ELISA. Theserum VEGF was found to be associated with T stage, but no association was seenwith nodal status. We also studied serum VEGF concentrations of 61 healthypersons (mean age: 63 years; male/female: 47/14). The serum VEGF concentrationsof healthy persons was 181  ± 165 pg/ml. This was lower than that ofpatients with NSCLC. Moreover, we studied serum VEGF concentrations aftersurgery. We obtained the sample at 1 to 3 months after surgery because woundhealing might increase the serum VEGF level through angiogenic responseimmediately after surgery. The serum VEGF was decreased after surgical resectionfrom 525 ± 442 pg/ml to 243 ± 214 pg/ml (detailed datanot shown). It appeared that the serum VEGF increased with growth of the tumorand also might reflect the tumor burden. A serum assay can be easily andfrequently performed because of its minimal invasiveness compared with surgicalexamination of resected tissue material. Dirix and associatesGo 26 reported that the serum VEGFmight prove a useful tool in the quantification of angiogenesis and might be ofvaluable information in the decision process of initiating palliativechemotherapy in colorectal cancer. Moreover, we think that an evaluation ofserum VEGF is useful for both a serologic diagnosis and the monitoring of thetumor burden. We have not yet checked serum VEGF in patients with recurrence,and we should examine the values for a longer period. In this study, there wasno significant association between the VEGF expression in tumor tissue and theserum VEGF concentrations. This discrepancy may be due to differences in the useof antibodies for each assay, such as anti-VEGF121 for IHC andanti-VEGF165 for ELISA. In addition, the mechanism of VEGF sheddingfrom the tumor cell to the systemic circulation has not yet been clearlyelucidated and may also be one of the reasons for this discrepancy.

The most interesting finding in this study was the prognostic impact ofVEGF expression in patients with completely resected NSCLC. Toi and associatesGo Go 27,28reported the VEGF expression to be a significant prognostic factor in patientswith breast cancer. However, there has been no report that shows the VEGFexpression to be associated with prognosis for patients with NSCLC. We foundthat the prognosis for patients with VEGF-positive tumor was significantly worsethan that for patients with VEGF-negative NSCLC. Harpole and associatesGo 29 have reported that angiogenesiswas the most significant prognostic factor in stage I lung cancer. In 32patients with stage I in this study, the VEGF expression was not significantprognostic factor (p = 0.12). However,only one of 13 patients with VEGF-negative tumor died. On the other hand, 6 of19 patients with VEGF-positive tumor died. Thus VEGF expression may be one ofthe most important prognostic factors in early stage lung cancer. According to amultivariate analysis using Cox's proportional-hazards regression model, theVEGF expression was found to be an independent significant prognostic factoralong with nodal status. Because the incidence of VEGF expression differedsignificantly between the patients with squamous cell carcinoma andadenocarcinoma, univariate and multivariate survival analyses were performed oneach histologic type. As a result, especially in patients with squamous cellcarcinoma, the expression of VEGF was found to be closely associated with theprognosis and to be an independent prognostic factor.

In conclusion, the VEGF expression is one of the most importantprognostic factors; the evaluation of the VEGF expression may be effective whenadjuvant therapy is considered for patients with completely resected NSCLC,including antiangiogenic therapy.Go 30


   Acknowledgments
 
We thank Kinue Nishida for her valuable technicalassistance.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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