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Annals of Surgical Oncology 8:260-267 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Vascular Endothelial Growth Factor and Soft Tissue Sarcomas: Tumor Expression Correlates With Grade

Celia Chao, MD, Tahseen Al-Saleem, MD, John J. Brooks, MD, André Rogatko, PhD, William G. Kraybill, MD and Burton Eisenberg, MD

From the Departments of Surgical Oncology (CC, BE), Pathology (TA-S), and Biostatistics (AR), The Fox Chase Cancer Center, Temple University Medical Center, Philadelphia, Pennsylvania, and the Departments of Surgical Oncology (WGK), and Pathology and Laboratory Medicine (JJB), Roswell Park Cancer Institute, Buffalo, New York.

Correspondence: Address correspondence and reprint requests to: Celia Chao, MD, Department of Surgery, University of Louisville, ACB Building, 2nd Floor, Louisville, KY 40292; Fax: 502-629-3183; E-mail: celia.chao{at}nortonhealthcare.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Introduction: Vascular endothelial growth factor (VEGF), an endothelial–specific mitogen overexpressed in various epithelial malignancies is thought to be a potent regulator of angiogenesis. We hypothesized that some soft tissue sarcomas, due to their high propensity for hematogenous metastases (1) would overexpress VEGF, (2) that the degree of expression may represent a significant biologic predictor for disease-specific survival, and (3) that recurrent tumor would express as high or higher VEGF compared with the primary tumor.

Methods: Selected paraffin-embedded tissue of surgical specimens from 79 patients with soft tissue sarcomas, treated between 1989 and 1995 were stained with a rabbit polyclonal anti-VEGF antibody at a concentration of 2 µg/ml. Slides were assessed for VEGF expression as high or low by two investigators blinded to the clinicopathologic data. Twelve patients had VEGF expression of their primary tumors, and their recurrent tumors were compared. The Fishers’ exact test assessed for differences in VEGF expression; survival analyses were performed according to the methods of Kaplan and Meier.

Results: Seventy-eight percent (29 of 37) of patients who died of disease had high VEGF expression. However, VEGF expression was not an independent predictor of either overall or disease-free survival. Tumor grade correlated with VEGF expression significantly. For the low-grade tumors, 7 of 13 expressed low VEGF, whereas for high-grade tumors, 53 of 66 expressed high VEGF (P = .016). Seven of the 12 paired tumor samples expressed identical VEGF immunostaining.

Conclusions: The majority of high-grade soft tissue sarcomas in this study have high intensity VEGF expression. This finding may provide useful information on individual soft tissue sarcomas and offer the basis for therapeutic and biologic targeting in high-risk patients using anti-angiogenesis strategies. However, in our analysis, after accounting for tumor grade, VEGF does not seem to be an independent predictor of clinical outcome.

Key Words: Vascular endothelial growth factor (VEGF) • Soft tissue sarcoma • Immunohistochemistry • Tumor grade


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The pathogenesis of neovascularization underlies the establishment, growth, and spread of many solid tumors.1 In these clonal cell populations, the normal equilibrium between cell proliferation and apoptosis is altered. Whether the pro-angiogenic factors (basic fibroblast growth factor and vascular endothelial growth factor) are initially upregulated or the inhibitors of angiogenesis (thrombospondin-1, angiostatin, endostatin) are suppressed is an area of intense scientific investigation.

The overexpression of vascular endothelial growth factor (VEGF) has been identified as a poor prognostic indicator in several different epithelial tumors such as breast, esophageal, gastric, and colorectal carcinoma.2–8 However, this finding has not been consistent in all reports, as other mediators of angiogenesis must play a role in epithelial malignancies such as squamous cancer of the head and neck.9 To date, there has been a paucity of reports on the expression of angiogenic factors in soft tissue sarcomas. In an effort to further understand the behavior of these tumors, VEGF expression was quantified and evaluated as a possible prognostic marker, along with tumor size, margin status at resection, tumor grade, and depth. Furthermore, because metastatic spread in these mesenchymal tumors is typically hematogenous, characterization of angiogenic factors may offer new therapeutic options for these tumors. We hypothesized that soft tissue sarcomas would (1) overexpress VEGF, (2) that the degree of VEGF expression may correlate with predictors of tumor aggressivity such as tumor grade and that it would also be an independent predictor of survival, and (3) that recurrent tumor would express as high or higher levels of VEGF compared with the primary tumors.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Characteristics
We retrospectively reviewed the charts of 79 soft tissue sarcoma patients from Fox Chase Cancer Center (FCCC) and the Roswell Park Cancer Institute (RPCI) between October of 1989 to December of 1995, with available histologic tissue from surgical specimens in the respective pathology departments. Clinicopathologic data were obtained from chart review at FCCC and a prospective database from RPCI. We recorded the type and location of soft tissue sarcoma resected, including pathologic grade, whether the tumor was primary or recurrent and whether the margins were negative (>=1 cm) or positive (<1 cm or tumor at the cut edge). The patients’ history of chemotherapy and/or radiation therapy, including brachytherapy was collected. Table 1 displays the clinical characteristics of the patients and the histopathologic details of the 79 patients. Their ages ranged from 15–89 years with a mean of 55.8 years. Fifty-three percent of the patients were male, and 73% of the tumors represented excision or marginal re-excision of the primary tumor. Follow-up period ranged from 1 to 264 months with a median of 48 months. Over half of the tumors were extremity sarcomas, and 24% were retroperitoneal sarcomas. Twelve patients had both primary tumor and recurrent, either local or metastatic, tumor available for VEGF immunohistochemical evaluation. One patient had both a local recurrence and a subsequent lung metastasis available for VEGF evaluation.


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  		TABLE 1. Characteristics of patients and their tumors (n = 79)
 
Immunohistochemistry
VEGF expression of the resected sarcoma specimens was evaluated using immunohistochemistry. Slides were selected to show tumor with normal adjacent tissue for purposes of comparison. All representative hematoxylin and eosin prepared slides were re-reviewed by two pathologists at FCCC (T.A.S.) and RPCI (J.B.). Five-micron sections were cut from selected formalin-fixed, paraffin-embedded tissue of surgical specimens. Antigen retrieval with 10 mM sodium citrate buffer, pH 6.0 was performed by boiling deparaffinized sections for 8 minutes using a 750 W microwave oven at low setting. Endogenous peroxidase activity was blocked with .4% hydrogen peroxide. The specimens then were preincubated in goat serum and stained with a rabbit polyclonal anti-VEGF antibody (A-20), capable of recognizing the 165, 189, and 121 amino acid splice variants of human VEGF by immunohistochemistry (Santa Cruz Biotechnology; Santa Cruz, CA). A concentration of 2 µg/ml of antibody was used. Negative controls were prepared by substituting the primary antibodies with nonspecific rabbit serum fluid. The peroxidase staining procedure was performed using the ABC Elite kit (Vector Laboratories, Burlingame, CA). The immunostaining reaction was visualized using .1% diaminobenzidine (DAB). All sections were counterstained with hematoxylin.

The frequency and intensity of the VEGF staining of the tumor cells was evaluated by two observers both blinded to the clinicopathologic data at a x400 optical field. A consensus of seven discordant cases was reached by reassessment on a double-headed microscope. With respect to the frequency of positive cells within tumors, it became apparent that nearly all cases displayed staining in 90% to 100% of the tumor cells. This was true in all but six tumor cases. However, the staining intensity varied significantly. Thus, the intensity of tumor staining was scored as follows: the VEGF expression was scored as "0" if negative, "1+" if weak or low intensity, "2+" if intermediate or moderate intensity, and "3+" for strong or high intensity. This method of scoring VEGF in tumor cells has been previously published.8 Peritumoral normal tissue containing endothelial cells or smooth muscle cells10 served as internal positive controls with an intensity score of "3+". In 4 cases, where the sarcoma was comprised of two different cell populations, the intensity of predominant cell population was recorded. For analyses, VEGF expression of the sarcomas was assigned to the category of "low" if a score of 0 or 1+ and "high" if a score of 2+ or 3+.

Statistical Analyses
Associations between prognostic factors were computed using the Fisher’s exact test. Survival data were defined from the time of initial diagnosis. Overall survival (OS) and disease-free survival (DFS) reflect disease-specific death or sarcoma recurrence respectively, and were analyzed using the methods of Kaplan and Meier. Univariate survival analyses of clinical factors which may be associated with prognosis were compared by the log rank test. Multivariate analyses were performed by using the Cox proportional hazards model and were fit to OS and DFS data. P values that were less than or equal to .05 were considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
VEGF Immunostaining and Clinicopathologic Correlations
Positive staining in all tumors was limited to the cytoplasm without membrane staining. In nearly all cases, staining was diffuse throughout the tumors. The vessels within the tumors stained intensely and were a strong internal control (Fig. 1). However, the intensity varied considerably among tumors and typical intensity staining patterns are depicted with their scores in Fig. 2. The intensity of VEGF protein staining in the tumor cells was correlated with various clinicopathologic factors (Table 2): patient gender, whether the tumor resected was primary versus recurrent (either local or metastatic), margins of resection, grade of the tumor (low or intermediate/high). Only tumor grade correlated with VEGF expression significantly (P = .016). Table 3 further demonstrates the trend between grade and VEGF expression; as grade increases, the percentage of high VEGF expression increases.




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  		FIG. 1. Comparison of tumor vascular endothelial growth factor (VEGF) immunostaining (score = 2+) and nearby endothelial cell (score = 3+).
TABLE 2. Correlation between VEGF expression and clinicopathologic factors
Variable VEGF expression
 P value
Low (0, 1+)
 High (2+, 3+)
Sex
    Male 12 30
    Female 8 29 .48
Margins
    Positivea 8 18
    Negative 12 41 .44
Tumor
    Primary 12 40
    Recurrent/metastatic 10 17 .19
Grade
    Low 7 6
    Intermediate/high
 13
 53
 .016b
VEGF, vascular endothelial growth factor.
a Margin, < 1 cm.
b Fisher’s two-tailed exact test, statistically significant.


TABLE 3. Tumor VEGF immunoreactivity and gradea
Grade VEGF
 % Cases with high VEGF
0
 1
 2
 3
 2 & 3
 3
Low 3 4 5 1 46 7.7
Intermediate 2 3 8 4 70.6 23.5
High 1 7 10 31 83.6 63
Total
79
a Fisher’s two-tailed exact test: P < .0001.

 
VEGF and Survival
Table 4 shows that on univariate analysis, age > 55 and the site of tumor (retroperitoneal versus other) negatively impacted on DFS only. Tumor grade on univariate (Table 4) as well as multivariate analyses (data not shown) was a powerful prognosticator of both DFS and OS. In fact, all patients with low-grade tumor are alive and free of disease (Table 5). Hence, for patients with low-grade tumors, median survival was not yet reached (Table 4). VEGF expression in the tumor was not an independent predictor of OS (Fig. 3) or DFS (Fig. 4), suggesting that tumor grade alone was the significant prognostic indicator. When the analysis was performed for intermediate and high-grade tumors only, VEGF expression still did not correlate significantly with either OS or DFS.


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  		TABLE 4. Univariate analysis of clinical factors associated with prognosis in sarcoma
 

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  		TABLE 5. Primary tumor and recurrent tumor: Comparison of VEGF expression
 


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  		FIG. 3. Kaplan Meier overall survival of soft tissue sarcoma patients by vascular endothelial growth factor (VEGF) immunostain intensity.

 


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  		FIG. 4. Kaplan Meier disease-free survival of soft tissue sarcoma patients by vascular endothelial growth factor (VEGF) immunostain intensity.

 
Comparison of VEGF Immunostaining of the Primary Tumor and Its Recurrence
Table 5 displays the differences in VEGF expression evaluated by immunohistochemistry between the 12 patients who had both primary tumor and recurrent tumor available. In seven of nine patients who received either chemotherapy or radiation therapy after resection of the primary tumor, there was no change in VEGF expression in the recurrent tumor. In the remaining two patients, there was a decrease in VEGF intensity from 2+ (moderate) to 1+ (low). Of interest, in the three patients without postoperative adjuvant therapy, there was one patient whose tumoral VEGF remained the same (3+), one patient with higher VEGF expression in the recurrent tumor (2+ to 3+), and one with lower VEGF expression in the recurrent tumor (3+ to 2+). Finally, one patient (MP) had a local recurrence that had the same low intensity VEGF expression as the primary tumor (1+) and a subsequent lung metastasis with high intensity of expression by VEGF immunostaining (3+).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Angiogenesis has been shown to play a key role in the maintenance, growth, and metastasis of many solid tumors.1 Wiedner et al. positively correlated blood vessel density with metastasis in human breast cancer.11 Most solid tumors secrete and overexpress VEGF, one of the potent activators of angiogenesis, although peritumoral inflammatory cells, such as macrophages, also may elaborate VEGF.8,12 There are five VEGF isoforms, derived from a single gene by alternative exon splicing; VEGF-165 and VEGF-121 seem to be the most abundant. Multiple epithelial tumors3–7 positively correlate VEGF expression with poor prognosis. Transfection of VEGF in a breast cancer cell line experimentally conferred increased vascularity and growth.13 Inhibition of VEGF is associated with growth suppression in a murine model of metastatic breast cancer to lung.14 Similarly, use of a small molecule inhibitor of VEGF receptor 2 (SU5416) caused regression of tumor derived from a neurogenic sarcoma cell line, which was implanted subcutaneously in mice compared with the control population.15

Despite interest in the study of angiogenic factors for many epithelial tumors, few clinical reports have addressed the angiogenic factors associated with soft tissue sarcomas.16–21 Graeven et al.19 showed that preoperative serum levels by enzyme-linked immunosorbent assay of VEGF and bFGF was significantly related to both tumor grade and tumor size. VEGF expression of osteosarcoma, which is highly responsive to multimodality therapy, was found to correlate significantly with the propensity for pulmonary metastatsis.21 However, Saenz et al. demonstrated that microvessel density (MVD), presumably the sum result of all anti- and pro-angiogenic factors, had no prognostic value in a series of patients with primary soft tissue sarcoma of the extremities.20 Additionally, Kawauchi et al.16 studied 54 primary synovial sarcomas, 12 of which were biphasic in nature, and found that VEGF expression of neither the tumor nor the nearby tumor-infiltrating inflammatory cells correlated with survival or tumor size. Results in the study were similarly not significant for MVD staining with regard to prognosis or survival. Furthermore, MVD of the tumor cells did not correlate with VEGF expression of the tumor cells. Our results support the aforementioned studies in soft tissue sarcomas, indicating that VEGF expression does not have independent prognostic significance associated with either DFS or OS.

Our study further confirms that grade is the single most important prognostic factor for patients with all types of soft tissue sarcoma. Importantly, this study is the first to demonstrate the strong correlation between tumor grade and VEGF immunostain intensity, which was suggested in the serum VEGF study by Graeven et al.19 This finding is dissimilar to the pattern seen in squamous cell carcinoma of the esophagus where, interestingly, increased VEGF expression correlated with well-differentiated and lower grade tumors.3

Our results between VEGF expression and grade is correlative, and it does not examine other angiogenic glycoproteins that are likely to be important. Salven et al.18 recently reported on two novel vascular endothelial growth factors, that are members of the VEGF family, named VEGF-B and VEGF-C. Northern blot analysis examined the varied mRNA expression levels of "original" VEGF, VEGF-B, and VEGF-C, all present in four types of sarcomas. For example, for a fibrosarcoma, the quantitative VEGF expression was only 2+, whereas VEGF-B and VEGF-C expressions were each 3+. Also, unlike epithelial tumors, VEGF may not be the predominant angiogenesis growth factor in some sarcomas. Emoto’s study of uterine carcinosarcomas showed that in 20 of 21 cases, MVD and VEGF expression by immunohistochemistry were significantly higher in the epithelial component compared with the mesenchymal elements, reflecting the clinical behavior of these biphasic tumors.22

The degree and type of VEGF expression for individual soft tissue sarcomas may offer a basis for specific therapeutic targeting in high-risk patients. In translational research studies, Wang et al. and Kim et al. independently reported suppression of growth in several sarcoma cell lines injected into nude mice treated with anti-VEGF monoclonal antibody.14,23 Further studies blocking VEGF receptors with nonfunctional dominant-negative constructs24 or the use of small molecule inhibitors15 on experimental sarcoma models confirm the importance of VEGF in the aggressive behavior of sarcomas as well as the suppression of such behavior with inhibitors of VEGF or VEGF receptors. Linder et al.17 have reported on the potential use of serum VEGF and bFGF to evaluate response to treatment (chemotherapy and/or radiation therapy). Serum VEGF measurements may be combined with immunohistochemical evaluation of tumors resected after treatment to further characterize the residual tumor after treatment.

Additionally, comparison of certain tumor markers in primary sarcomas and their metastatic deposits may offer further understanding of resistant clonal populations that may have emerged after treatment with chemoradiation. In a study of 22 patients by Tarkkanen et al., comparative genomic hybridization was performed on DNA samples from the primary sarcoma and from matching pulmonary metastasis. All paired samples revealed both shared genetic alterations as well as important differences in DNA sequence copy numbers during the progression of disease.25 In our series of paired samples, the majority of tumors that recurred locally or metastasized to distant sites preserved their VEGF intensity status. How this relates to gene expression and protein function is unknown at this time. Differences between the primary and the metastatic tumor may provide additional information relative to soft tissue sarcomas’ propensity for pulmonary metastases and underlie the strategies for therapeutic targeting. Current therapies have not specifically targeted tumor grade or VEGF expression. Clinical trials are necessary to establish whether cytotoxic chemotherapy combined with angiostatic compounds can have an impact on the survival of high-risk sarcoma patients.


   Acknowledgments
 
We are grateful to Deborah Malik and Deborah Driscoll for their invaluable assistance with the specimens and data from RPCI.


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

Received for publication June 14, 2000. Accepted for publication December 4, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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