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10.1245/ASO.2006.08.012
Annals of Surgical Oncology 13:1054-1062 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Prognostic Significance of Vascular Endothelial Growth Factor Expression and Microvessel Density in Esophageal Squamous Cell Carcinoma: Comparison With Positron Emission Tomography

Joon Young Choi, MD1, Kee-Taek Jang, MD2, Young Mog Shim, MD3, Kwhanmien Kim, MD3, Geunghwan Ahn, MD2, Kyung-Han Lee, MD1, Yong Choi, PhD1, Yearn Seong Choe, PhD1 and Byung-Tae Kim, MD1

1 Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Korea
2 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Korea
3 Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-ku, Seoul 135-710, Korea

Correspondence: Address correspondence and reprint requests to: Byung-Tae Kim, MD; E-mail: btkim{at}smc.samsung.co.kr.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: This study investigated whether the expression of vascular endothelial growth factor (VEGF) in a primary tumor and the intratumoral microvessel density (MVD) were independent prognostic factors in patients with an esophageal squamous cell carcinoma (SCC) in comparison with positron emission tomography (PET) by using 18F-fluorodeoxyglucose (FDG) and stage.

Methods: Fifty-one patients with a newly diagnosed esophageal SCC who underwent preoperative FDG-PET and esophagectomy with intent to cure were enrolled in this study. The VEGF expression level, the intratumoral MVD, and the Ki-67 labeling index were evaluated by using immunohistochemical staining. Only significant variables in the univariate survival analysis were examined by multivariate survival analysis with the Cox proportional hazards model.

Result: Cancer-related deaths occurred in 17 of 51 patients during the follow-up. Univariate survival analysis showed that the pathologic stage, pNM, maximum standardized uptake value of the primary tumor, tumor length on PET, number of PET-positive lymph nodes, PET stage, Ki-67 labeling index, intratumoral MVD, and the presence of VEGF expression were significant prognostic predictors for the overall survival. Multivariate analysis revealed that the pathologic stage, number of PET-positive nodes (0, 1, 2, or ≥3), intratumoral MVD (cutoff, 60/mm2), and presence of VEGF expression were independentsignificantprognostic predictors for overall survival.

Conclusion: In addition to the pathologic stage, the intratumoral MVD, the presence of VEGF expression, and the number of FDG-PET–positive nodes were independent prognostic predictors in patients with an esophageal SCC undergoing curative surgery.

Key Words: Esophageal cancer • Positron emission tomography • 18F fluorodeoxyglucose • Angiogenesis • Prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
A squamous cell carcinoma (SCC) of the esophagus has a generally unfavorable prognosis. Therefore, a proper assessment of the prognosis is crucial for selecting the appropriate treatment and planning the follow-up. The depth of invasion and the presence of lymph node metastases based on the tumor-node-metastasis system are independent prognostic variables in esophageal SCC.1 However, there is some controversy as to the accuracy of the current staging system in evaluating the prognosis of esophageal cancer, because it does not reflect other independent prognostic factors, such as the angiogenic molecular markers, the number of malignant lymph nodes, and the tumor length.

Many studies reported that angiogenic molecular markers, such as the vascular endothelial growth factor (VEGF) expression of the primary tumor and the intratumoral microvessel density (MVD), were significant prognostic factors in esophageal cancer.2 However, there was some disagreement. Only a few studies used multivariate analysis to evaluate the prognosis, and there are some discrepant results between those studies. For VEGF expression, some studies have reported that it is an independent prognostic factor,3–5 but others have reported otherwise.6–8 For MVD, some studies have shown it to be an independent prognostic factor,7,9 but others have not.3,4,10 Most studies either did not include the stage as a variable for survival analysis or the stage was determined not to be an independent prognostic factor on multivariate analysis. VEGF expression and MVD can be acquired accurately only after an open esophagectomy, which is frequently associated with significant morbidity and mortality.11 Therefore, their clinical utility has not been established in esophageal cancer.

The number of malignant lymph nodes and the tumor length have been suggested to be independent prognostic factors in esophageal cancer.12–15 Positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) has shown good results for the noninvasive initial staging of esophageal cancer.16,17 It was recently reported that the number of PET-positive lymph nodes and the tumor length measured by PET, along with the pathologic stage, were independent prognostic factors in esophageal SCC.18 There are no reports showing an association between the angiogenic molecular markers and the FDG-PET findings with the prognosis after curative surgery in esophageal SCC.

This study examined whether the VEGF expression level in the primary tumor and the intratumoral MVD were independent prognostic predictors in patients with esophageal SCC undergoing curative surgery in comparison with those obtained by using FDG-PET and stage.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
A total of 89 consecutive patients with a newly diagnosed esophageal cancer between February 1997 and May 2000 were initially included in this study. All the patients underwent a conventional staging work-up and FDG-PET within 3 weeks of the diagnosis. In this study, all patients without any distant organ metastasis or definite evidence of extensive tumor invasion to the adjacent organs were routinely subjected to an extensive regional lymph node dissection along with an esophageal resection. The presence of an extensive or distant lymph node metastasis such as upper abdominal nodal metastasis or cervical nodal metastasis in intrathoracic esophageal cancer was not considered to be a contraindication for a surgical resection, as long as the nodes were included in the primary resection field, because this is associated with better survival than visceral metastases and has an approximately 10% of chance of cure at 5 years after surgical resection.1,12–14 The ethics committee of this institution approved the protocol, and informed consent was obtained from all subjects.

Among 89 cases, 10 were inoperable: 4 patients demonstrated distant metastatic lesions on the pre-operative staging tests (including FDG-PET), 3 showed evidence of a direct invasion to the adjacent organs (main bronchus, thyroid gland, or epiglottis), 2 had a medical condition that was too poor to overcome surgery, and 1 showed malignant omental seeding on a laparotomy. Nine patients had surgically resectable disease, but they refused surgery. The remaining 70 patients underwent esophagectomy. The R0 resection of the primary mass was not accomplished in one patient, and this patient was excluded from further analysis. Another 18 patients were excluded because of a loss of the paraffin block including the primary tumor or a small tumor volume for immunohistochemical staining. Therefore, a final total of 51 patients with esophageal SCC were enrolled in this study.

Immunohistochemical Staining
After an initial review of all the available hematoxylin and eosin (H&E)-stained slides of the surgical specimens, one paraffin-embedded tissue block was selected from each case for which the tumor margin and viable tumor cells were present. Serial 3-µm sections were made from each block. The first section from each case was stained with H&E again, the second was immunostained for the Ki-67 antigen, the third was immunostained for VEGF, and the fourth was immunostained for the CD34 antigen to acquire the MVD. Immunostaining was performed by using the avidin-biotin peroxidase complex method. Anti-human VEGF mouse monoclonal immunoglobulin G antibody (Santa Cruz Biotechnology, Santa Cruz, CA), the anti-CD34 mouse monoclonal antibody (Dako, Glostrup, Denmark), or the anti–Ki-67 monoclonal antibody (Dako) was used as the primary antibody. 3,3-Diaminobenzidine was used as the chromogen, and hematoxylin was used as the counterstain. For the negative controls, all the reagents were used except for the primary antibody.

All the slides were coded and evaluated by an experienced pathologist, who had no knowledge of the patient’s identity or clinical status. The cell types with positive staining for VEGF were defined morphologically by using H&E staining. The case was considered VEGF positive when intensive positive staining of VEGF was observed in >10% of the tumor cells.

The degree of angiogenesis was determined by the MVD in defined areas of the tissue sections that immunostained for the CD34 antigen. Each microvessel counting was performed twice. Each slide was first scanned at a x100 magnification to determine three hot spots, which were defined as areas with the maximum number of microvessels. The slides were then examined at x200 magnification by using a calibrated grid. The number of microvessels was counted within the area defined in each of the three hot spots. The staining area with no discrete breaks was counted as a single vessel. The intratumoral MVD was estimated by adding the number of vessels in each of the three hot spots and is expressed as the mean number of vessels per square millimeter.

A dark accumulation of 3,3-diaminobenzidine in the nuclei indicated a positive reaction for Ki-67. The percentage of positive nuclei stained for Ki-67—i.e., the Ki-67 labeling index (LI)—was calculated for each section based on the approximately 1000 carcinoma cell nuclei. Figure 1Go shows representative slides of immunohistochemical staining. Positive staining corresponds to a dark brown color.


Figure 1
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  		FIG. 1. A panel of representative immunohistochemical staining in esophageal squamous cell carcinoma (original magnification, x400). A high vascular density by CD34 endothelial staining (A, arrows) is associated with highly positive nuclear staining by the Ki-67 antigen (B, arrows) and positive cytoplasmic vascular endothelial growth factor expression (C, arrows).

 
PET Imaging
All the patients fasted for at least 6 hours before the PET study. The PET scans were performed with a GE Advance PET scanner (GE Healthcare, Milwaukee, WI). The emission scans were performed from the thigh to the head for 5 minutes per frame 45 minutes after the intravenous injection of 370 MBq of FDG. The tomographic images were reconstructed without attenuation correction by filtered back-projection with a Hanning filter (cutoff frequency, 8.0 mm). In addition, the attenuation-corrected images of the thorax and/or upper abdomen level were acquired by reconstruction by using the 10-minute postemission transmission or preinjection transmission images with Germanium-68 rods.

The tomographic images, which were displayed as coronal, sagittal, and transaxial slices, were viewed on a HP workstation (Hewlett-Packard Company, Palo Alto, CA). Two nuclear physicians, who were blinded to the immunohistochemical staining and histological results, reviewed together and interpreted the PET images by consensus. The maximum standardized uptake value (SUV) of the primary mass was acquired by using the attenuation-corrected images, the amount of FDG injected, the body weight of each patient, and the cross-calibration factors between the PET and the dose calibrator. The tumor length was measured from the number of transaxial slices where the primary tumor had been observed. In other words, the number of transaxial slices with the primary tumor multiplied by the slice thickness corresponded to the tumor length. Lymph nodes were considered to be positive for a malignancy if there was focal prominent FDG uptake, compared with the normal mediastinal activity, found in two or more consecutive transaxial slices. The number of PET-positive nodes and the PET stage (N0M0, N1M0, or M1) in each patient were recorded.1

Staging
The conventional preoperative clinical stage of each patient was determined by bone scintigraphy, esophagogastroduodenoscopy, bronchoscopy, endoscopic ultrasonography, abdominal ultrasonography, and a computed tomographic (CT) scan of the chest and upper abdomen. Abdominal or neck CT scans and neck ultrasonography were performed when clinically indicated. The detailed protocol and the interpretation of the CT and endoscopic ultrasonography are described elsewhere.16

All the patients underwent transthoracic en-bloc esophagectomy with either a two-field (thoracoabdominal; n = 44) or three-field (thoracoabdominal and cervical; n = 7) extensive lymph node dissection, except for one patient, who underwent a transhiatal esophagectomy. One thoracic surgeon dissected all the visible or palpable lymph nodes within the surgical field, taking into consideration all the results from the preoperative studies, including FDG-PET. Each dissected nodal group was labeled by using the modified lymph node mapping system for esophageal cancer,16 and the nodes of each group were examined histopathologically for the presence of malignant cells. In addition, the location, depth, length, cell type, and degree of differentiation of the resected primary tumor were examined histopathologically. The tumor-node-metastasis system was used to determine the clinical and pathologic stage of each patient.1

Clinical Follow-Up
Adjuvant therapy, including radiotherapy and chemotherapy after surgery or palliative therapy after a recurrence, was performed according to each patient’s situation, the physician’s decision (mainly based on the presence of pathologic lymph node metastasis), and the patient’s medical condition (including performance status). After surgery, all the patients were monitored regularly to obtain accurate information regarding a recurrence. A follow-up program was initiated every 2 to 4 months during the first year, every 4 to 6 months during the next 2 years, and every year thereafter. Every follow-up evaluation included a complete physical examination, a complete blood count, biochemical screening, and a chest radiograph. CT scans of the chest and upper abdomen were performed every 6 months to 1 year or more frequently if clinically indicated. Other tests, including barium contrast esophagography, esophagogastroduodenoscopy, and ultrasonography/CT of the neck and abdomen, were also performed where clinically indicated.

Recurrence or metastasis was considered when there was a finding suggesting a recurrence or a metastasis on serial imaging studies or a pathologically confirmed malignancy. The events for survival analysis were defined as a recurrence or metastasis and a cancer-related death. The disease-free and overall survival durations to the last follow-up were recorded for each patient.

Data Analysis and Statistics
The Kaplan-Meier method was used to estimate the disease-free and overall survival rates for each variable. The equivalences of the survival curves were tested by using log-rank statistics. The Cox proportional hazards model with the likelihood ratio statistics based on the conditional parameter estimate was used to evaluate the independent prognostic variables for multivariate survival analysis.

The clinical variables for univariate survival analysis included age, sex, location of the primary tumor, histological grade of the primary tumor, clinical and pathologic stages, pT, pNM, maximum SUV of the primary tumor, tumor length measured by PET, number of PET-positive nodes, PET stage, Ki-67 LI, MVD, and the presence of VEGF expression. Continuous variables were grouped to enter the survival analysis. Grouping cutoff points of continuous variables, such as maximum SUV or MVD, were determined retrospectively to reflect the best prognosis. Only those variables found to be significant by univariate survival analysis (P < .1) were examined by multivariate survival analysis. The numerical data are expressed as the mean ± SE for the survival data and the mean ± SD for the others.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Demographic Data
Table 1Go shows the patient and tumor characteristics. The mean age at the time of diagnosis was 63 ± 7 years (range, 41–77 years). More than 90% of the patients were male. Most tumors originated from the middle and lower esophagus. All the patients with stage IV disease had a nonregional lymph node metastasis without a distant organ metastasis. Postoperative adjuvant therapy was performed in 26 of 51 patients (chemotherapy only in 14 and chemotherapy and radiotherapy in 12). The mean clinical follow-up duration was 36 ± 27 months.


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  		TABLE 1. Characteristics of the patients with esophageal cancer included in the study and the univariate survival analysis results
 
Immunohistochemical Staining Data
VEGF expression was found in 21 (41.2%) of the 51 cases. The mean intratumoral MVD was 50.7 ± 9.9/mm2 (range, 34.9–78.5/mm2). The mean Ki-67 LI was 26.5% ± 8.9% (range, 10%–42%). The intratumoral MVD (58.5 ± 8.2/mm2 vs. 45.3 ± 7.0/ mm2; P < .001) and Ki-67 LI (34.8% ± 3.5% vs. 20.7% ± 6.7%; P < .001) were significantly higher in the subgroup of patients with positive VEGF expression than in those with negative VEGF expression. A significant linear correlation was found between the MVD and Ki-67 LI (R = .58; P < .001). The maximum SUV of the primary tumor had no significant relationship with the presence of VEGF expression, MVD, or Ki-67 LI.

Survival Data
At the time of the last follow-up, 25 patients were alive and had no evidence of disease, 3 were alive with recurrent esophageal cancer, 17 had died from esophageal cancer, and 6 had died as a result of an intercurrent illness (n = 4) or postoperative complications (n = 2). Univariate survival analysis showed that the performance of adjuvant therapy, the pathologic stage, pNM, the number of PET-positive nodes, and the intratumoral MVD were significant prognostic predictors for the disease-free survival (Table 1Go). Multivariate analysis showed that both pNM and intratumoral MVD were independent significant prognostic predictors for disease-free survival (Table 2Go).


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  		TABLE 2. Significant variables on multivariate survival analysis for predicting the disease-free survival and overall survival
 
Univariate survival analysis showed that the pathologic stages, pNM, maximum SUV of the primary tumor, tumor length on PET, number of PET-positive nodes, PET stage, Ki-67 LI, intratumoral MVD, and the presence of VEGF expression were significant prognostic predictors for overall survival (Table 1Go). Multivariate analysis revealed that the pathologic stage, the number of PET-positive nodes, the intratumoral MVD, and VEGF expression were independent significant prognostic predictors for overall survival (Table 2Go; Figs. 2Go–4GoGo).


Figure 2
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  		FIG. 2. Overall survival curves according to the number of positron emission tomography–positive nodes.

 

Figure 3
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  		FIG. 3. Overall survival curves according to the intratumoral microvessel density.

 

Figure 4
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  		FIG. 4. Overall survival curves according to the presence of vascular endothelial growth factor expression.

 
When the patients were subgrouped according to the pathologic stage, the overall survival was significantly different according to the intratumoral MVD in the subgroup of patients with pathologic stages II, III, and IV (Table 3Go). The overall survival in the subgroup of patients with pathologic stage IV was significantly different according to the presence of VEGF expression (estimated 5-year overall survival: 42.2% ± 14.7% [n = 13] vs. .0% ± .0% [n = 9]; P = .03).


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  		TABLE 3. Overall survival by the intratumoral MVD in the subgroup of patients divided by pathologic stage
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Angiogenesis is essential for tumor progression and metastasis. Accordingly, many studies using histological sections of the primary tumors have shown that MVD and VEGF expression in an esophageal SCC reflect the level of angiogenesis and are associated with tumor progression and metastasis.2–10 This study compared the intratumoral MVD, the presence of VEGF expression, and FDG-PET findings with the prognosis after curative surgery in esophageal SCC. Patients with a VEGF-negative or low-MVD cancer had a superior survival outcome compared with those with a VEGF-positive or high-MVD cancer. The number of PET-positive lymph nodes was also significantly associated with the prognosis. Moreover, multivariate analysis showed that in addition to the pathologic stage, MVD, the presence of VEGF expression, and the number of PET-positive nodes were independent prognostic factors for overall survival in esophageal SCC.

Significant correlations were found between the presence of VEGF expression, MVD, and Ki-67 LI. This suggests that the presence of VEGF expression and the increased proliferative activity may result in an increase in the MVD, although the angiogenic potential is believed to be regulated by a balance between different angiogenic substances.2–10 The intratumoral MVD was a single independent prognostic indicator for both the disease-free and overall survival. When patients were subgrouped according to the pathologic stage, the overall survival was significantly different according to the intratumoral MVD in the subgroup of patients with pathologic stage II, III, and IV (Table 3Go). In particular, no events occurred in the subgroup of patients with pathologic stage II or III and a low MVD during the clinical follow-up. This suggests that the intratumoral MVD might be a better prognostic indicator than the presence of VEGF expression in an esophageal SCC, even though the hazard ratio of VEGF expression shown in multivariate analysis was higher than that of MVD. In contrast, the maximum SUV of a primary tumor showed no significant relationship with the MVD, VEGF expression, or Ki-67 LI. This suggests that the metabolic activity of a primary tumor is not related to tumor angiogenesis or the proliferative activity in an esophageal SCC.

There are some issues that need to be resolved for VEGF expression and MVD to be used routinely. First, the different criteria used for defining positive VEGF expression and a high MVD are the most challenging issue. For positive VEGF expression, 10%, 30%, 50%, and 80% cutoffs have been used.3–5,7,8 For a high MVD, various cutoffs such as 40/mm2, 60/mm2, 116/mm2 and 145/mm2, per x200 microscopic field have been used.3,4,9,10 This study adopted a 10% cutoff for VEGF expression7,8 and a 60/mm2 cutoff for MVD,4 which reflected the best prognosis in these results.

Second, an accurate evaluation of VEGF expression and MVD requires an adequate amount of the primary tumor, which can usually be obtained by an esophagectomy. Therefore, the role of VEGF expression and the MVD in determining the treatment and follow-up plan at the time of the initial tumor staging is limited. A recent study showed that it was possible to measure the MVD by using a pre-treatment biopsy specimen and it was an independent prognostic factor in esophageal cancer after chemoradiotherapy. However, the pathologic stage and FDG-PET findings were not included in the variables for survival analysis.19 Further study will be needed to evaluate the value of MVD and VEGF expression by using a pretreatment biopsy specimen.

Controversial results were found in previous studies on using MVD and VEGF expression as an independent prognostic factor.2–10 Different cutoffs for high MVD and positive VEGF expression may be one of the causes. Most studies did not describe the surgical methods in detail.3–10 In this study, a transthoracic en-bloc esophagectomy with extensive lymph node dissection was performed in all subjects except for one, which is suggested to bring on more accurate staging and better survival.20,21 This may also contribute to the discrepant results.

The current staging system for an esophageal carcinoma classifies the positive lymph nodes as being either regional or metastatic disease (stage IV) according to the location of the lymph node and the location of the primary tumor. In addition, it does not consider the number of malignant lymph nodes.1 However, these results showed that the number of metastatic lymph nodes was an independent prognostic factor, which was similar to results reported elsewhere.12–14 Recently, Eloubeidi et al.14 proposed a new tumor-node-metastasis classification system for esophageal carcinoma which considered the number of positive nodes. These results also supported this new staging system. If the staging system were to be revised to consider the number of malignant nodes, FDG-PET might become more useful for the initial noninvasive staging of esophageal cancer, on account of its good results for predicting the prognosis.

Esophageal cancer is one of the malignancies with a poor prognosis. After an R0 esophagectomy, adjuvant therapy such as chemotherapy or radiotherapy does not improve survival.22,23 Therefore, a new effective therapy is needed after surgery to improve survival in esophageal cancer. Recently, several antiangiogenic molecules have been developed and are under clinical investigation for cancer treatment.24,25 This study found that a high MVD or the presence of VEGF expression was associated with a poor prognosis in patients with the same pathologic stage. In this clinical situation, antiangiogenic therapy may be considered in patients with a high-MVD or positive-VEGF esophageal SCC after surgery.

This study has several limitations. The small number of patients is a major limitation of this study, particularly for multivariate analysis. In addition, other predictors might be considered to be independent variables in a larger study population. Because of the limited number of subjects, we were unable to analyze the survival data by dividing the stage II cases into stages IIA and IIB, which have demonstrated a different prognosis. Finally, there were no subjects with adenocarcinoma of the esophagus in this study. Two patients had adenocarcinoma but were excluded from further analysis because of their refusal of surgery. A very low prevalence of esophageal adenocarcinoma is a typical finding of esophageal cancer in East Asian countries, including Korea. Currently, there was no definite evidence of differences in prognosis between SCC and adenocarcinoma of esophagus.1,15 Thus, this may not affect our results significantly.

In conclusion, in addition to the pathologic stage, the intratumoral MVD, the presence of VEGF expression, and the number of FDG-PET–positive nodes were independent prognostic predictors in patients with an esophageal SCC undergoing curative surgery. These results support a revised tumor-node-metastasis classification system for an esophageal carcinoma by considering the number of malignant lymph nodes to be an important prognostic factor. In the near future, it may be possible to perform adjuvant therapy by using angiogenesis inhibitors in patients with an esophageal SCC after surgery based on the combined use of the tumor-node-metastasis stage and the angiogenic molecular markers, including VEGF expression and intratumoral MVD.


   ACKNOWLEDGMENTS
 
This study was supported by a grant of the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (02-PJ3-PG6-EV06-0002).

Received for publication August 5, 2005. Accepted for publication January 6, 2006.


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TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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