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10.1245/s10434-006-9286-3
Annals of Surgical Oncology 14:1431-1438 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Assessment of Clinical Outcome in Patients With Esophageal Squamous Cell Carcinoma Using TNM Classification Score and Molecular Biological Classification

Shinsuke Takeno, MD, PhD, Tsuyoshi Noguchi, MD, PhD, Yoshiaki Takahashi, MD, PhD, Shoichi Fumoto, MD, Tomotaka Shibata, MD and Katsunobu Kawahara, MD, PhD

Department of Oncological Science (Surgery II), Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Yufu-City, Oita 879-5593, Japan

Correspondence: Address correspondence and reprint requests to: Shinsuke Takeno, MD, PhD; E-mail: takeno{at}med.oita-u.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The aim of this study was to assess the clinical outcome in patients with esophageal squamous cell carcinoma (ESCC) by using molecular biological classification based on immunohistochemical analysis in addition to tumor, node, metastasis system (TNM) classification.

Methods: Samples from 71 patients with ESCC who underwent surgery were analyzed immunohistochemically. Cyclin B1, E-cadherin, Bag-1, and heat-shock protein 70 were selected as the molecular biological parameters. The utility of molecular biological classification on clinical impact was examined and compared with TNM classification.

Results: Three patients were diagnosed as stage 0, 14 as stage I, 20 as stage II, 19 as stage III, and 15 as stage IV by TNM classification. Thirteen patients were classified as stage 0, 17 as stage I, 21 as stage II, 18 as stage III, and 2 as stage IV by molecular biological classification. Molecular biological stage (P < .0001) and TNM stage (P < .0001) were statistically significant prognostic parameters in univariate analysis. Twenty (28.2%) of 71 patients were assigned to the same stage by both classifications, and a significant correlation was identified between the two classifications (P = .0002). Molecular biological classification (P < .01) and TNM classification (P < .0001) were independent prognostic parameters in multivariate analysis. Combined TNM and molecular biological classification accurately reflected clinical outcome (P < .0001).

Conclusions: Molecular biological classification combined with TNM classification is useful for assessing the prognosis of patients with ESCC.

Key Words: Clinical outcome • ESCC • TNM classification • Molecular biological classification • Cyclin B1 • HSP70 • E-cadherin • BAG-1


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Despite the development of multimodal therapy combining surgery, irradiation, and chemotherapy, patients with esophageal cancer continue to exhibit unfavorable clinical outcomes.1 Although the incidence of esophageal adenocarcinoma is increasing in the West, the predominant histology of esophageal cancer remains squamous cell carcinoma worldwide, particularly in the East, including Japan.2

The tumor, node, metastasis system (TNM) of classification by the International Union Against Cancer (UICC) is commonly used in the assessment of clinical outcome in patients with esophageal squamous cell carcinoma (ESCC).3 However, TNM classification merely reflects cancer progression status at the time of diagnosis. In contrast, molecular biological analysis has clarified biological behavior in cancer progression, and several molecular biological parameters have been reported to be prognostic factors in various malignancies. Our institute has identified several molecular prognostic parameters for ESCC.4–7 These analyses use immunohistochemical staining, an easy and popular technique that can be performed in most laboratories that currently use hematoxylin-eosin staining for pathological diagnosis by pTNM classification.

The aim of the present study was to examine the possibility of prognostic assessment of patients with ESCC by using our published molecular biological parameters. For the present study, we selected various prognostic parameters reflecting different potentials.4–10 We also examined the usefulness of a prognostic assessment score that combined TNM and molecular biological classification to establish a prognostic assessment system.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
A total of 101 patients with esophageal cancer underwent surgery in our institute between January 1990 and December 1997. Of 101 patients with esophageal cancer, 97 patients (96.0%) were diagnosed as ESCC by histology, and 71 patients with ESCC (63 men and 8 women; mean age, 63.8 years; range, 43–84 years) without evidence of residual cancer (R0 resection) were included in the study. Surgical treatment comprised resection of the esophagus with extended two- or three-field lymph node dissection. We excluded patients who had received preoperative supplemental (neoadjuvant) therapy, patients with disease with direct invasion to other organs or distant organ metastasis, and patients with tumors diagnosed as other histological type. Resected specimens were classified according to the TNM classification system developed by the UICC.3

The mean and median follow-up periods were 34.4 and 40.0 months, respectively (range, 3–60 months). We assessed patients for recurrence of disease every 3 months by computed tomographic scan without adjuvant therapy. If disease recurred, we treated the patient with chemotherapy or chemoradiotherapy with 5-fluorouracil and cisplatin.

The patients in the present series all provided informed consent. We received institutional review board permission to conduct the study.

Immunohistochemical Staining
Detailed methods have been described previously.4–7 Immunohistochemical staining was performed by a standard avidin-biotin complex method with a streptavidin-biotin-peroxidase kit (Nichirei, Tokyo, Japan). 3,3'-Diaminobenzidine was used as the chromogen. Countersaining was performed with hematoxylin. The antibodies used in the immunohistochemical staining were anti–cyclin B1 monoclonal antibody Novocastra (Newcastle Upon Tyne, UK), anti–BAG-1 monoclonal antibody Dako (Glostrup, Denmark), anti–heat shock protein 70 (HSP70) polyclonal antibody Scytek (Logan, USA) and anti–E-cadherin monoclonal antibody (Novocastra). Tonsil for cyclin B1, breast cancer for BAG-1, and normal esophageal mucosa for HSP70 and E-cadherin were used as a positive control in the immunohistochemistry. Two independent observers (S.T., T.N.) with experience in pathology and immunohistochemistry and who were masked to the prognostic information evaluated the samples in each immunohistochemical staining series.

Evaluation of immunohistochemical staining has been described in our previous reports.4–7 Briefly, cases of positive cytoplasmic reaction of more than 20% cancer cells were evaluated as "high" in cyclin B1; cases of positive nuclear reaction of more than 50% cancer cell were evaluated as "positive" in Bag-1; cases of positive reaction in the cell membrane or cytoplasm of less than 50% cancer cells were evaluated as "reduced" in E-cadherin; and cases of positive cytoplasmic reaction of less than 50% cancer cells were evaluated as "negative" in HSP70. These four findings comprise the group with unfavorable prognosis (Table 1Go).


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  		TABLE 1. Prognostic scoring system
 
Scoring for Molecular Biological Classification and Prognostic Assessment Score
A favorable prognostic factor was scored as 0, and an unfavorable prognostic factor was scored as +1 (Table 1Go). The total score from four parameters was adopted as the molecular biological stage. The combined score of TNM and molecular biological classification was adopted as the prognostic assessment score (Table 2Go).


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  		TABLE 2. Tumor, node, metastasis system of classification combined with molecular biological classification of stage
 
Statistical Analysis
Overall survival was calculated according to the Kaplan-Meier method from the time of surgery to either death or date of last follow-up. The log rank test was used to determine statistical differences between life tables. The Cox proportional hazard regression model was used for multivariate analysis. Correlation between TNM and molecular biological classification was analyzed by Spearman’s correlation test. A P value of <.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Overall survival of all patients in the present series is shown in Fig. 1Go. Three patients were diagnosed as stage 0, 14 as stage I, 20 as stage II, 19 as stage III, and 15 as stage IV by the TNM classification. Several patients survived for long periods despite diagnoses of stage III or IV disease by the TNM classification system.


Figure 1
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  		FIG. 1. Overall survival of all patients.

 
Thirteen patients were classified as stage 0, 17 as stage I, 21 as stage II, 18 as stage III, and 2 as stage IV by the molecular biological classification system. All patients classified as stage 0 survived, and all classified as stage IV died within 10 months. However, the prognostic distinction between stages I, II, and III was not clear with this classification system. The prognostic impact of each molecular biological parameter in each stage was analyzed, and only statistically significant prognostic impacts of HSP70 expression were observed in stage III of TNM classification (P = .0247). However, no other significance was revealed (Table 3Go).


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  		TABLE 3. Prognostic implication of molecular biological parameters in each stage by tumor, node, metastasis system classification
 
In the present series, molecular biological stage (P < .0001) and TNM stage (P < .0001) were identified as statistically significant prognostic parameters by univariate analysis (Figs. 2Go and 3Go). Of 71 cases, 11 were classified as being at a more progressive stage by the molecular biological system than by TNM classification, and 40 were classified as less progressive (Tables 4Go and 5Go). Twenty cases (28.2%) were classified as the same stage by the two systems, and a significant correlation was observed between the two classifications (P = .0002) (Table 5Go). In addition, the survival in each stage by TNM classification could be distinctly separated by molecular biological stage, although the difference failed to reach statistical significance (Fig. 4Go). Despite a significant correlation, both TNM classification (P < .0001) and molecular biological classification (P < .01) were identified as independent prognostic parameters by multivariate analysis (Table 6Go).


Figure 2
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  		FIG. 2. Survival after surgery by tumor, node, metastasis system (TNM) of classification. There was a significant difference in survival after esophagectomy by TNM classification (P < .0001). Stage 0 vs. 1, P = .6434; 0 vs. 2, P = .1881; 0 vs. 3, P = .0414; 0 vs. 4, P = .0093; 1 vs. 2, P = .0195; 1 vs. 3, P = .0001; 1 vs. 4, P = .0001; 2 vs. 3, P = .0520; 2 vs. 4, P = .0001; 3 vs. 4, P = .0193.

 

Figure 3
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  		FIG. 3. Survival after surgery by biological molecular classification. There was a significant difference in survival after esophagectomy by both molecular biological classification and TNM classification (P < .0001). Stage 0 vs. 1, P = .0023; 0 vs. 2, P = .0006; 0 vs. 3, P = .0001; 0 vs. 4, P = .0001; 1 vs. 2, P = .8094; 1 vs. 3, P = .1782; 1 vs. 4, P = .0031; 2 vs. 3, P = .1951; 2 vs. 4, P = .0114; 3 vs. 4, P = .0544.

 

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  		TABLE 4. Summary of prognosis and cancer stage
 

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  		TABLE 5. Correlation between TNM classification and molecular biological stagea
 

Figure 4
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  		FIG. 4. Prognostic significance by molecular biological (MB) classification in (a) stage I, (b) stage II, (c) stage III, and (d) stage IV of the tumor, node, metastasis system (TNM) of classification. No prognostic importance in each TNM stage was found between favorable and unfavorable stage by molecular biological classification. However, survival could be separated relatively distinctly.

 

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  		TABLE 6. Multivariate analysis of survival in patients with esophageal squamous cell carcinoma
 
Three patients were classified as stage 0, 13 as stage I, 19 as stage II, 29 as stage III, and 7 as stage IV by the prognostic assessment classification in which TNM classification was adjusted by molecular biological stage. This classification more clearly reflected the clinical outcome of the patients with ESCC in the present series (P < .0001) (Fig. 5Go). All patients evaluated as stage 0 had favorable clinical outcomes and survived. In contrast, all patients at stage IV had unfavorable prognoses and died within a year.


Figure 5
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  		FIG. 5. Survival after surgery by the combined tumor, node, metastasis system (TNM) of classification and molecular biological stage. Prognostic significance was clearly revealed by the score (P < .0001). Stage 0 vs. 1, P = .6310; 0 vs. 2, P = .2467; 0 vs. 3, P = .0308; 0 vs. 4, P = .0086; 1 vs. 2, P = .0652; 1 vs. 3, P = .0001; 1 vs. 4, P = .0001; 2 vs. 3, P = .0045; 2 vs. 4, P = .0001; 3 vs. 4, P = .0001.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
TNM classification is a useful parameter for predicting the outcome of patients with ESCC and various malignant tumors.3 However, it only reflects cancer progression status at the time of diagnosis, and some patients may survive for a long time while others with disease in the same TNM stage may have a more unfavorable prognosis. Therefore, more distinct clinical assessments are required. Such assessments may depend on molecular biological characteristics such as tumor proliferative activity, metastatic potential, or apoptosis. We have previously reported several biological prognostic parameters in 71 patients with ESCC in a single consecutive series. However, vascular endothelial growth factor C (VEGF-C), fragile histidine triad (FHIT), or galectin-3 could not be prognostic parameters in ESCC, and so they were not adopted for this study.8–10 Therefore, cyclin B1, E-cadherin, Bag-1, and HSP70 were the molecular prognostic parameters we chose to evaluate cell proliferation, metastasis, apoptosis, and cancer immune response, respectively.4–7 In the present study, we found that molecular biological classification could be a prognostic parameter independent of TNM classification.

In TNM classifications, stages I, II, and III exhibited relatively distinct clinical outcomes, although some patients with progressive cases of stage IV disease survived for a long time and several patients with early-stage disease had unfavorable outcomes. In contrast, the molecular biological classification successfully distinguished between cases with favorable or unfavorable outcome as stage 0 or IV, respectively, although the prognosis could not be distinguished among stages I, II, and III. According to this result, we theorized that combining these classifications could more accurately predict prognosis in patients with ESCC after surgery. Furthermore, each molecular biological parameter could not reflect a distinct prognosis of TNM classification, except the prognostic impact of HSP70 in stage III (Table 3Go). By contrast, the survival in each TNM stage could be separated relatively distinctly by molecular biological classification (Fig. 3Go). By taking them into consideration, our results suggest that a comprehensive molecular biological analysis that combines several malignant potentials, not just a single molecular parameter, could be used to adjust the TNM classification and predict a clinical outcome.

Some cases were assigned to discrepant stages by the two systems, which exhibited correlation (Tables 4Go and 5Go). This may explain why patients in the same TNM stage often have different clinical outcomes. All patients diagnosed in stage 0 by TNM classification were also assigned to stage 0 by molecular characteristics, and all survived more than 5 years. This means that ESCC classified in stage 0 by TNM classification can be cured by early detection and surgical treatment. In contrast, some cases classified as relative early stage I by TNM classification were found to have progressive malignant potential by molecular biological system assessment, and other cases were found to be of low molecular biological malignant potential despite advanced TNM stage classification. This discrepancy suggests that cancer does not always have biological malignancy potential in proportion to cancer development. Some patients may require multimodal therapy despite early TNM stage. Therefore, a prognostic assessment system that combines TNM and molecular biological classifications may help clinicians tailor treatments to each patient.

To date, only a few studies have reported the use of biological characteristics identified by immunohistochemical analysis for clinical classification.11–13 These studies also selected a group of molecular biological parameters to reflect various biological characteristics, and they reported the usefulness of molecular grading in assessing prognosis in ESCC. However, to our knowledge, the present report is the first to describe the use of prognostic assessment that combines TNM classification and molecular biological classification.

Proper selection of molecular biological parameters is crucial for success of this classification system. In the present study, we mainly selected parameters from those reported in the literature.4–7,14–17 It should be kept in mind that the prognostic parameters selected for the present study did not have equivalent prognostic impacts, although the prognosis could be reflected by simply selecting only these four molecular parameters from our published data. For example, although cyclin B1 and E-cadherin were identified as independent prognostic parameters by multivariate analysis, HSP70 and Bag-1 were prognostic factors, but not independent ones. Therefore, the combination used in this study may not be optimal because four molecular parameters were scored as having equal importance on clinical outcome. Furthermore, this study does not include parameters that take into account the role chemoradiotherapy plays in recurrence. Prognostic accuracy might be improved by changing the scoring weight of these molecular parameters, or by supplementing the prognostic parameters we used with other parameters for chemoradiotherapeutic sensitivity reported by other investigators. Further study is required to learn which stages by TNM or molecular biological classification do not have equal prognostic impact; molecular data may be nothing but the adjustable prognostic parameters for TNM classification.

Recently, comprehensive analysis by gene profiling using microarray analysis for molecular biological characterization of ESCC has been developed to study other cancers.18–20 However, the equipment and array chips are currently expensive, and it analyzes many thousands of genes simultaneously, including many genes meaningless to ESCC. In contrast, immunohistochemical staining is a relatively easy, popular technique that does not require expensive equipment and can be performed in most laboratories. Thus, clinical application of this immunohistochemical methodology, which uses several essential prognostic parameters, is likely to be cost-effective in the near future. The use of targeted tissue arrays containing tens or hundreds of important prognostic parameters will further improve the accuracy of clinical outcome assessments in patients with breast, colorectal, and lung cancers.21–26

In conclusion, the present study demonstrates the use of a prognostic assessment system that combines TNM and molecular biological classifications using immunohistochemistry in patients with ESCC. This system may be useful in future clinical applications. For example, adjuvant chemotherapy might be considered in patients diagnosed with advanced-stage disease adjusted by molecular biological classification despite early TNM stage classification. An optimized treatment could thus be targeted for each patient. Future studies with more patients are required to assess the clinical applications of adjuvant chemotherapy.

Received for publication September 23, 2006. Accepted for publication November 1, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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