Abstract
Objective
Esophageal cancer tumor biology is best assessed clinically by FDG-PET. Both FDG-PET SUVmax and selected tumor markers have been shown to correlate with stage, nodal disease, and survival in esophageal cancer. Interestingly, there is limited data examining the relationship between FDG-PET SUVmax and expression of these tumors markers in esophageal cancer. The purpose of this study was to determine the correlation of tumor markers with FDG-PET SUVmax in esophageal cancer.
Methods
FDG-PET SUVmax was calculated in 67 patients with esophageal cancer of which 59 (88%) had adenocarcinoma. Neoadjuvant radiotherapy and/or chemotherapy were administered to (28/67) 42% of patients. Esophageal tumor tissue and surrounding normal tissue was obtained and tissue microarrays were created. Immunohistochemical analysis was performed for 5 known esophageal cancer tumor markers (GLUT1, p53, cyclin D1, EGFR, and VEGF). Assessment of each tumor marker was made by two independent, blinded pathologists using common grading criteria of intensity and percentage of cells stained. A p-value < 0.05 was considered significant.
Results
There were 55 men (82%) and 12 women (18%) with a median age of 63 years (range 40-83). Pathologic staging included stage I (N=29, 43%), stage II (N=19, 28%), stage III disease (N=18, 27%), and stage IV disease (N=1, 2%). PET SUVmax correlated with T stage (p=0.001). In patients undergoing surgery without induction therapy, increasing SUVmax values correlated with increased expression of GLUT1 transporter (p=0.01). There was no correlation between SUVmax and EGFR, cyclin D1, VEGF, or p53 expression in primary tumor.
Conclusions
FDG-PET SUVmax correlates with an increased expression of GLUT1 transporter in esophageal cancer specimens not subjected to induction therapy. No significant difference in tumor marker expression was noted between patients undergoing induction therapy or surgery alone except p53 expression decreased in primary tumors following induction therapy. Failure of SUVmax values to correlate with known prognostic esophageal cancer tumor markers suggests that FDG-PET may have limited clinical utility in assessing response to therapies targeting these markers.
Keywords: esophageal cancer, tumor markers, FDG-PET
Introduction
FDG-PET is a valuable tool in the staging of esophageal cancer by quantitating biological activity of primary tumor sites and detecting evidence of metastatic disease. A recent multicenter prospective randomized trial demonstrated the utility of FDG-PET in detecting esophageal cancer metastasis not found by conventional workup [1]. Maximal PET standardized uptake values (SUVmax) of the primary tumor have been shown to predict overall survival in patients with esophageal cancer [2, 3]. Furthermore, the change in SUVmax (delta SUVmax) following induction therapy for esophageal cancer has been shown to correlate with pathologic response [4]. Also, a 60% reduction in SUVmax following induction therapy was significantly associated with improved disease-free survival [5]. Therefore, measurement of glucose utilization by FDG-PET adds significant diagnostic and prognostic value to the evaluation of patients with esophageal cancer.
While the classical TNM staging system includes well-known prognostic pathological factors of esophageal cancer, this system offers no assessment of the biologic or molecular associated with the development and progression of esophageal cancer. Molecular pathology has provided considerable information regarding the differential expression of genes and molecules associated with esophageal carcinogenesis [6]. Many of these differentially expressed genes and proteins have been shown to be tumor markers for disease progression and, as such, are the targets for several novel molecularly targeted therapies.
The five tumor markers selected for evaluation in this study were GLUT-1, p53, EGFR, VEGF, and cyclin D1. These markers were selected based upon previous reports highlighting an important link with the development or progression of esophageal cancer [7-18].
Increased glucose uptake in tumor cells is thought to be regulated by glucose transporter activity [19]. Overexpression of GLUT-1, the human erythrocyte glucose transporter, has been correlated with poor prognosis in patients with squamous esophageal cancer and has been associated with progression of the Barrett's metaplasia-dysplasia-adenocarcinoma sequence [9, 15].
Changes in the tumor suppressor gene expression of p53 are an early and frequent event in the pathogenesis of esophageal adenocarcinoma [11]. p53 protein overexpression has been found in 36% of esophageal adenocarcinoma specimens [8, 18]. Previous work has suggested the p53 mutations and/or overexpression in esophageal adenocarcinoma is a predictor of reduced postoperative survival following esophageal resection [8].
Epidermal growth factor receptor (EGFR) is overexpressed in 30-60% of esophageal adenocarcinoma tumors. Higher EGFR expression has been correlated with significantly poorer survival [16].
Cyclin D1, an important cell cycle regulator, becomes deregulated in esophageal adenocarcinoma [10]. In patients with Barrett's esophagus, cyclin D1 expression was found to be present in 67% of specimens that later developed adenocarcinoma compared to 29% who did not develop adenocarcinoma [7]. Hence, cyclin D1 alterations have become a potential biomarker for the progression of esophageal adenocarcinoma.
Vascular endothelial growth factor (VEGF) plays a critical role in tumor metastasis. Several studies have demonstrated increased VEGF expression with conversion of Barrett's metaplasia to esophageal adenocarcinoma [12, 13]. VEGF expression has been correlated with a poor prognosis in squamous esophageal cancer [14].
As previous clinical studies have demonstrated the significant utility of FDG-PET in correlating pathologic stage and prognosis in esophageal cancer, the detection of tumor markers in primary esophageal tumors and their correlation to FDG-PET uptake may provide critical information regarding the key molecular mechanisms important for the progression of esophageal carcinogenesis. Currently, no studies have investigated whether SUVmax or delta SUVmax in patients completing induction therapy correlate with different tumor marker expression as compared to patients undergoing surgery alone.
Utilizing esophageal cancer tissue microarrays, this study examines the correlation of the above listed tumor markers to the best known non-invasive surrogate marker of tumor biology, FDG-PET. Through subgroup analysis of patients undergoing induction therapy compared to surgery alone, we investigate whether expression patterns of the selected tumor markers and respective correlations with SUVmax are different between groups. Overall, the goal of the study is to characterize the relationship of FDG-PET and the selected tumor markers with the goal of providing further insight into the pathogenesis of esophageal carcinoma.
Materials and Methods
Patients
Paraffin-embedded primary esophageal tumor samples and patient-matched normal esophageal tissue (N=67) were collected between 2005 and 2007. Approval for collection of the patient tissue was obtained from the Institutional Review Board for Health Science Research at the University of Virginia. Individual patient consent was obtained for procurement of tissue for research purposes prior to patients undergoing induction therapy and/or surgery alone. Clinicopathologic data was collected using our General Thoracic Surgery database. Table 1 shows the demographic characteristics of the patients included in this study.
Table 1.
Patient Characteristics
| Variable | Surgery Alone (N=40) | Induction Therapy (N=27) | P-value |
|---|---|---|---|
| Median age (years) * | 67 (range= 44-80) | 57 (range=40-70) | 0.05 |
| Sex (M:F)† | 32 (80%): 8 (20%) | 23 (85%): 4 (15%) | 0.91 |
| Pre-Induction SUVmax | 5.5±3.4 | 8.6 ± 4.0 | 0.03 |
| Post-Induction SUVmax | NA | 3.6 ± 1.4 | |
| Adenocarcinoma (%)† | 35 (88%) | 24 (89%) | 0.89 |
| Pathological Staging† | |||
| I | 18 (45.0%) | 10 (37.1%) | 0.86 |
| II | 11 (27.5%) | 8 (29.6%) | 0.91 |
| III | 10 (25.0%) | 8 (29.6%) | 0.95 |
| IV | 1 (2.5%) | 1 (3.7%) | 0.67 |
| Clinical Staging† | |||
| I | 16 (40.0%) | 0 (0%) | 0.002 |
| IIA | 11 (27.5%) | 11 (44.0%) | 0.19 |
| IIB | 3 (7.5%) | 1 (4.0%) | 1.0 |
| III | 10(25.0%) | 7 (48.0%) | 0.78 |
| IVA | 0 (0%) | 1 (4.0%) | 1.0 |
Mean±SD Mann-Whitney t-test performed with significance p<0.05
Fisher Exact Test performed with significance p<0.05
PET/CT Analysis
Integrated PET-CT scanner (Siemens Biograph Duo, Siemens Medical Solutions, Knoxville, TN.) was used for all patients. The patients fasted for at least 4 h prior to intravenous injection of approximately 15 mCi (555 MBq) 2-[18F]fluoro-2-deoxy-d-glucose (FDG). The examination was performed approximately 45 min post injection with the patient positioned supine with the arms placed over the head. Imaging was performed with arms down in patients who could not keep the arms over the head. CT scans were performed immediately prior to the PET scan with the dual-detector spiral CT scanner without administration of oral or intravenous iodinated contrast. The PET scan followed immediately with an acquisition time of 5 min per bed position during shallow breathing. CT and PET imaging extended from the base of the skull through the pelvis.
The standardized uptake value (SUV) is a decay-corrected measurement of activity per unit of volume of tissue (nCi/mL) adjusted for administered activity per unit of body weight (nCi/kg). Any site of suspicious FDG accumulation not located in areas of physiological increased uptake was considered a lesion and evaluated semi-quantitatively by determining the standardized uptake value using the software supplied with the scanner and a 50% threshold and software supplied with the scanner. The radiologist drew an irregular region of interest (ROI) around each lesion, and the maximum SUV was reported.
Of the 67 patients, 86% of patients had their FDG-PET scan performed and interpreted at the University of Virginia. The remaining 14% of patients had their FDG-PET imaging performed at an outside institution with interpretation of the studies independently reviewed at the University of Virginia.
All patients that underwent induction therapy had pre-therapy FDG-PET imaging performed as well as repeat FDG-PET imaging following the completion of induction therapy to detect the delta SUVmax (ΔSUVmax) of the primary tumor following completion of induction therapy. Patients completing induction therapy were imaged 4-6 weeks post-therapy and had their operations 1-2 weeks after imaging.
Preparation of the TMAs
All tumor slides were reviewed for tumor type and grade by two pathologists blinded to FDG-PET results. A representative slide and the corresponding block of formalin-fixed paraffin embedded tissue were selected. For each case, three 1 mm cores of tumor and 1 core of uninvolved adjacent epithelium were removed from the original block and embedded in a paraffin block using a specialized manual arraying instrument (Model MTA1, Beecher Instruments, Sun Prairie, WS). In cases that showed a complete pathologic response scar tissue was used in place of tumor.
Immunohistochemical Analysis and Pathologist Scoring
A tissue microarray was constructed for immunohistochemical studies that evaluated p53, VEGF, EGFR, cyclin-D1, and GLUT1. Information for the antibody, antigen retrieval mechanism and staining pattern is summarized in Table 2. Immunohistochemical staining was scored using the product of percent of tumor cell positivity and intensity (0 = none; 1= weak; 2 moderate; 3 = intense). Scores ranged from 0 to 300%.
Table 2.
Antibodies for Immunohistochemical Analysis
| Antibody | Company | Catalog # | Type | Clone | Dilution | Antigen Retrival | Positive Staining Pattern |
|---|---|---|---|---|---|---|---|
| VEGF | DAKO | M7273 | Monoclonal Mouse | VG1 | 1/6400 | Citrate Buffer | Cytoplasmic |
| EGFR | DAKO | M3563 | Monoclonal Mouse | H11 | 1/400 | Citrate Buffer | Cytoplasmic |
| p53 | DAKO | M7001 | Monoclonal Mouse | DO-7 | 1/50 | Citrate Buffer | Nuclear |
| GLUT-1 | DAKO | A3536 | Polyclonal Rabbit | Not available | 1/300 | Citrate Buffer | Cytoplasmic Membrane |
| Cyclin D1 | DAKO | M7155 | Monoclonal Mouse | DCS-6 | 1/50 | Citrate Buffer | Nuclear |
Statistical Analysis
Statistical analysis was performed using SAS version 9.1 for Windows (SAS Institute, Cary, North Carolina). The correlation of preoperative SUVmax with clinico-pathological factors and tumor marker expression was analyzed using the Spearman rank test with calculation of 95% confidence intervals. To determine differences in tumor marker expression and clinico-pathologic factors between the two treatment groups (surgery alone vs. induction therapy), the Mann-Whitney test or Fisher exact test was used where appropriate. Differences in tumor marker expression based upon SUVmax values were tested using Mann–Whitney test for non-parametric distributions. Differences were considered significant when the p value was less than 0.05.
Results
There were 67 patients with esophageal cancer included in this study. Forty patients underwent surgery without induction therapy and 27 patients underwent induction therapy prior to surgical resection. The demographic characteristics of the two groups are shown in Table 1. In the induction therapy group, 93% (25/27) of patients had both chemotherapy and radiation therapy while 7% (2/27) had only chemotherapy. Median age was 67 years in patients undergoing surgical resection alone compared to 57 years in patients undergoing induction therapy prior to surgery (p=0.05). Adenocarcinoma was present in 88% of the patients. Endoscopic ultrasound was performed on 79% of patients for staging. Mean interval between initial PET/CT scan and post-induction therapy PET/CT scan was 3.7±2.7 months. Clinical staging of the patients is also shown in Table 1. Staging of the induction therapy group represents post-induction therapy. Post-induction therapy staging was not available for 2 patients. The patient with stage IV disease in the induction therapy group demonstrated a hypermetabolic celiac node on PET/CT following induction therapy.
Histopathologic and tumor marker analysis data are presented in Table 3. Measurement of the pathologic greatest tumor dimension between treatment groups showed an increased tumor size in the patients undergoing surgery alone compared to those having received induction therapy. Nodal disease and M1a disease were not significantly different between groups. The p53 product in the surgery alone group was significantly higher when compared to the induction therapy group (p=0.01). Interestingly, p53 tumor cell positivity was not different between groups (p=0.14). GLUT-1, EGFR, Cyclin D1, and VEGF expression were not significantly different between treatment groups. GLUT-1 was detected in 50% of tumors in the surgery alone group and 36% of the induction therapy group (p=0.33).
Table 3.
Histopathology and Tumor Marker Immunohistochemistry
| Variable | Surgery Alone | Induction Therapy | P-value |
|---|---|---|---|
| Pathologic Tumor Greatest Dimension | 3.6±2.4 cm | 2.2±1.9 cm | 0.01 |
| pN1 | 13 (32.5%) | 12 (44.4%) | 0.63 |
| pM1a | 0 (0%) | 1 (3.7%) | 1.0 |
| Pathologic Complete Response | NA | 6 (22%) | |
| Lymphovascular Invasion | 16 (40%) | 10 (37%) | 0.87 |
| Necrosis | |||
| Mild | 32 (80%) | 20 (75%) | 0.86 |
| Moderate | 8 (20%) | 7 (25%) | 0.78 |
| Inflammation | |||
| Mild | 15 (37%) | 9 (33%) | 0.91 |
| Moderate | 25 (63%) | 18 (67%) | 0.91 |
| Tumor Marker Immunopositivity | |||
| GLUT-1 positive | 20 (50%) | 10 (36%) | 0.33 |
| GLUT-1 product | 57 ± 96 | 45 ± 94 | 0.22 |
| p53 positive | 34 (85%) | 18 (68%) | 0.14 |
| p53 product | 108 ± 104 | 56 ± 88 | 0.01 |
| EGFR positive | 10 (26%) | 3 (11%) | 0.21 |
| EGFR product | 11± 23 | 5 ± 23 | 0.14 |
| Cyclin D1 positive | 31 (78%) | 18 (67%) | 0.39 |
| Cyclin D1 product | 59 ± 70 | 48 ± 78 | 0.15 |
| VEGF positive | 7 (18%) | 5 (18%) | 1.0 |
| VEGF product | 18 ± 49 | 28 ± 68 | 0.46 |
Data presented as mean±SD
Mann-Whitney test or Fisher's Exact Test performed with significance defined as p<0.05
We next examined whether tumor markers or histological features correlated with FDG-SUV maximal uptake in the two groups. Table 4 lists the Spearman correlation coefficients, 95% confidence intervals, and corresponding p-values for the measured variables relative to SUVmax. In the surgery alone group, greatest tumor dimension (p<0.0001), pathologic stage (p=0.003), T stage (p=0.0005), and necrosis (p=0.02) positively correlated with increasing SUVmax. With induction therapy, only T-stage significantly correlated with increasing SUVmax (p=0.01) while greatest tumor dimension (p=0.07) and pathologic stage (p=0.06) did not quite reach statistical significance. The percentage of GLUT-1 positive cells and the GLUT-1 product demonstrated a significant positive correlation with increasing SUVmax for the surgery alone group but not the induction therapy group. Figure 1 illustrates GLUT-1 expression in esophageal cancer primary tumor microarrays. Although no other correlations with SUVmax were found to be significant, the correlation coefficients for all non-significant variables were within the 95% confidence intervals thereby preventing one from concluding that such variables could be excluded as clinically relevant to SUVmax. Further stratification of the induction therapy group was performed to determine if the difference between SUVmax pre- and post-induction therapy would uncover statistically significant correlations between ΔSUVmax and tumor markers or histologic characteristics. However, this analysis found only delta SUVmax positively correlated with T stage (p=0.003).
Table 4.
FDG –PET SUVmax, Histopathology Variables, and Tumor Marker Expression
| Variable | Treatment Groups | |||
|---|---|---|---|---|
| Surgery Alone | Induction Therapy | |||
| Correlation Coefficient (95% CI) | P-value | Correlation Coefficient (95% CI) | P-value | |
| Histopathology | ||||
| Greatest tumor dimension | 0.72 (0.51-0.84) | <0.0001 | 0.36 (-0.04-0.66) | 0.07 |
| Path Stage | 0.46 (0.16-0.68) | 0.003 | 0.36 (-0.03-0.66) | 0.06 |
| T Stage | 0.53 (0.24-0.72) | 0.0005 | 0.53 (0.09-0.78) | 0.01 |
| N Stage | 0.23 (-0.09-0.51) | 0.16 | 0.11 (-0.29-0.48) | 0.58 |
| Lymphovascular invasion | 0.32 (-0.006-0.58) | 0.05 | 0.07 (-0.42-0.53) | 0.78 |
| Necrosis | 0.36 (0.04-0.61) | 0.02 | -0.02 (-0.41-0.37) | 0.91 |
| Inflammation | 0.15 (-0.18-0.44) | 0.38 | 0.13 (-0.27-0.49) | 0.53 |
| Tumor Marker Expression (%) | ||||
| GLUT-1 | 0.40 (0.09-0.64) | 0.01 | 0.16 (-0.24-0.51) | 0.44 |
| p53 | -0.04 (-0.36-0.28) | 0.79 | -0.09 (-0.46-0.30) | 0.66 |
| EGFR | 0.18 (-0.15-0.47) | 0.27 | 0.20 (-0.20-0.54) | 0.32 |
| Cyclin D1 | 0.30 (-0.02-0.56) | 0.06 | -0.24 (-0.57-0.17) | 0.24 |
| VEGF | 0.05 (-0.28-0.36) | 0.78 | 0.04 (-0.36-0.42) | 0.85 |
CI=Confidence Intervals
Figure 1.
GLUT-1 Tissue Microarray of Esophageal Cancer
A. Representative tissue microarray of GLUT-1 expresson in esophageal cancer demonstrates differential expression patterns between patient tumor samples.
B. 10× magnification illustrating diffuse GLUT-1 expression in esophageal adenocarcinoma.
C. 40× magnification illustrating GLUT-1 expression in esophageal adenocarcinoma.
Since tumor GLUT-1 expression correlates with SUVmax in the surgery alone group, we further evaluated the relationship by determining the significance of increased GLUT-1 expression with increasing SUVmax. SUVmax values and the corresponding GLUT-1 immunopositivity and GLUT-1 product values for patients undergoing surgery alone is shown in Table 5. In the surgery alone group, tumors with a SUVmax of > 10.0 averaged 45% of tumor cells expressing GLUT-1 which was significantly higher than tumors with SUVmax of 0-2.5 which averaged only 3.5% of tumor cells expressing GLUT-1 (p=0.01).
Table 5.
FDG-PET SUVmax and GLUT-1 Expression (Surgery Alone)
| SUVmax | N | GLUT-1 Percentage * | GLUT-1 Product * | ||
|---|---|---|---|---|---|
| 0-2.5 | 10 | 3.5±6.7 | 5.5±12.6 | ||
| 2.6-5.0 | 12 | 13.3±27.0 | p=0.31 | 32.1±73.8 | p=0.28 |
| 5.1-10 | 11 | 30.9±39.2 | p=0.05 | 91.8±118.4 | p=0.04 |
| >10 | 7 | 45.0±41.1 | p=0.01 | 115.0±113.8 | p=0.01 |
Expressed as Mean ± SD
Discussion
This study has investigated the correlation of 5 tumor markers with FDG-PET, the best non-invasive method of assessing tumor biology in esophageal cancer. As FDG-SUVmax has been correlated with poorer survival in previously published studies [2, 3], further examination of tumor markers may provide insight into the mechanisms important for esophageal carcinogenesis.
SUVmax was found to positively correlate with the expression of GLUT-1 in surgically resected primary esophageal tumors not subjected to induction therapy. GLUT-1 activity signals enhanced glycolytic metabolism which has been correlated with tumor proliferative activity [20]. Previously published studies have demonstrated that GLUT-1 overexpression in esophageal squamous cell carcinoma is an independent risk factor of death [15]. Prior to this investigation, no studies have investigated the relationship of GLUT-1 or other tumor marker immunohistochemical expression profiles with FDG-PET in esophageal adenocarcinoma. With nearly 90% of our patients diagnosed with esophageal adenocarcinoma, this study suggests that GLUT-1 expression does correlate with FDG-PET SUVmax.
We found no difference between other tumor marker expression and SUVmax regardless of whether the patient had induction therapy or surgery alone. In fact, the only difference noted in tumor marker expression was that the p53 product calculation was significantly lower in tumors following induction therapy compared to patients that underwent surgery alone. Heeren et al previously reported that decreased p53 expression in patients following chemotherapy for esophageal adenocarcinoma was predictive of a positive chemotherapeutic response and improved survival [21]. Although ΔSUVmax was assessed, this did not correlate with the five investigated tumor markers.
EGFR expression in esophageal adenocarcinoma has been correlated to common histopathologic parameters including T stage, N stage, and M stage [16]. Previous work has noted a correlation of FDG-PET SUVmax with clinical response to EGFR inhibitors in non-small cell lung cancer [22]. Robust response to EGFR inhibitors in NSCLC was attributable to activating EGFR mutations including the in-frame deletion delE746-A750 and the missense L858R [23]. No studies have evaluated the correlation of FDG-PET to EGFR expression in esophageal cancer. One previous study of 17 adenocarcinoma specimens found the same two activating EGFR mutations which predicted robust EGFR inhibitor response in NSCLC [23]. However, despite the presence of the same mutations in esophageal adenocarcinoma, clinical response to EGFR inhibition in esophageal adenocarcinoma has been modest [23]. Therefore, the importance of EGFR regulation may in fact be significantly different between the two types of cancer. While no study has investigated the correlation of FDG-PET with response to EGFR inhibitors in esophageal cancer, our initial results suggest that FDG-PET may be a poor non-invasive modality to track EGFR inhibitor response in esophageal adenocarcinoma.
Failure to demonstrate a significant correlation between FDG-PET and VEGF expression in primary esophageal tumor is supported by previous work in 89 patients performed by Choi and colleagues [24]. This suggests that the metabolic activity of the primary tumor as assessed by FDG-PET may not be related to tumor angiogenesis. While no study has investigated the use of FDG-PET to monitor clinical response to anti-VEGF therapies such as bevacizumab in esophageal cancer, this data suggest that FDG-PET may also be a poor correlate for clinical response to anti-VEGF therapy.
Cyclin D1 expression in esophageal tumors did not correlate with FDG-PET SUVmax in this study. No previous studies have investigated the relationship between FDG-PET and cyclin D1 expression in esophageal cancer, however, in lung adenocarcinoma, cyclin D1 expression did not correlate with FDG-PET SUV [25]. Our data suggest that metabolic activity of the primary esophageal tumor as measured by FDG-PET may be unrelated to regulators of the cell cycle.
Complete pathologic response (PCR) to induction therapy was noted in 6 patients. Post-induction therapy FDG-PET SUVmax values ranged from 1.3 to 3.2 in this group. Evaluation of the reminant scar at the location of the primary tumor found expression of GLUT-1 in 2 patients, p53 in 3 patients, EGFR in 1 patient, cyclin D1 in all 6 patients, and VEGF in 1 patients. No patients in this group have had recurrent disease although length of follow-up is limited. No studies have investigated the importance of residual immunohistochemical staining of tumor markers in scars from primary esophageal tumors following PCR to induction therapy. The presence of these residual tumor markers following a pathologic complete response may indicate remaining microscopic disease and further investigation of this subpopulation of patients is warranted.
Limitations of this study include the limited sample size utilized in this study. A larger sample size may elucidate further relationships between FDG-PET and the investigated tumor markers. Second, utilizing tissue microarrays in which small tissue cylinders are studied may not in fact adequately represent the entire specimen due to tissue heterogeneity. Third, immunohistochemical analysis also has inherent drawbacks including interlaboratory differences in antigen retrieval, staining protocols, and antibodies utilized. A fourth limitation is that PET/CT imaging was not performed on the same scanner for 14% of this cohort which could influence the interpretation of SUVmax. However, 86% of patients did have PET/CT imaging on the same scanner. We attempted to address the potential discrepancies of the 14% that received PET/CT imaging outside of our institution by interpreting the results at our institution. Since 2005, the prognostic implications of 30 or more genes and molecules involved in esophageal adenocarcinoma have been investigated [6]. With only 5 tumor markers investigated in this study, significant work to investigate other tumor markers and their correlation with FDG-PET must be performed.
In conclusion, GLUT-1 expression correlates with FDG-SUVmax in patients with esophageal cancer not subjected to induction therapy. Comparison of tumor marker expression between patients undergo induction therapy with those undergoing surgery alone demonstrated that p53 expression is downregulated in esophageal tumors following induction therapy. Finally, the inability to find a significant correlation between SUVmax and both EGFR and VEGF expression in esophageal cancer suggests monitoring clinical response to pharmacologic inhibition of these proteins by FDG-PET may be challenging.
Footnotes
Presented at the 16th Annual Meeting of the European Society of Thoracic Surgeons Bologna, Italy, June 8-11, 2008
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