Tumor Length as a Prognostic Factor in Esophageal Squamous Cell Carcinoma

Tumor Length as a Prognostic Factor in Esophageal Squamous Cell Carcinoma Bing-Yen Wang, MD,* Yih-Gang Goan, MD, PhD,* Po-Kuei Hsu, MD, Wen-Hu Hsu, MD, and Yu-Chung Wu, MD

Background. Tumor size is an important prognostic factor in many cancers, but its role in esophageal cancer remained undetermined. The aim of this study is to investigate the impact of tumor length on survival for patients with resected esophageal squamous cell carcinoma. Methods. A total 582 esophageal squamous cell carcinoma patients underwent surgical resection as the primary treatment was enrolled into this retrospective review. The longitudinal tumor length was defined as a uniformly measurement from the surgeons in the operating room immediately after completion of the esophagectomy. The impact of tumor length on patient’s overall survival was assessed and compared with the factors among the current tumor-nodes-metastasis (TNM) staging system published in 2009. Results. The overall 1-, 3-, and 5-year survival rates were 70.4%, 37.8%, and 30.0%, respectively, with a median for 22 months. The length adversely affected the

overall survival, and the 5-year survival rate was 77.3%, 48.1%, 38.5%, and 23.3 % for tumor lengths of 1 cm, 2 cm, 3 cm, and more than 3 cm, respectively (p < 0.001). In multivariate survival analysis, tumor length (more or less than 3 cm) remained an independent prognostic factor (p ⴝ 0.020) as did the other current TNM factors. For subgroup analysis, the predictive value of tumor length was significant in patients with T1 or T2 disease (p < 0.001), T3 or T4 disease (p ⴝ 0.029), and patients with N0 disease (p < 0.001), but not for patients with N1, N2, or N3 disease. Conclusions. Tumor length, which represents longitudinal spreading of the cancerous cells, could impact the overall survival of patients with resected esophageal squamous cell carcinoma, especially among those with nodal-negative disease. It may provide additional prognostic information to the current TNM staging system. (Ann Thorac Surg 2011;91:887–93) © 2011 by The Society of Thoracic Surgeons

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therapy were enrolled to clarify the prognostic effect of tumor length in ESCC patients. The relationship between surgical longitudinal tumor length incorporating the seventh edition AJCC TNM staging system and long-term survival was evaluated in a large series of patients with ESCC.

egardless of chemoradiation therapy or surgical management, the prognosis of esophageal squamous cell carcinoma (ESCC) remains poor. Many clinicopathologic factors predicting the outcome of ESCC patient have been reported in past 10 years [1-3]. In the newly published edition of the American Joint Committee on Cancer (AJCC) TNM staging system, histological grading and tumor location as well as depth of esophageal wall invasion are regarded as prognostic factors for both adenocarcinoma and squamous cell carcinoma. Several previously published results indicated that tumor length was an independent predictor of survival in esophageal cancer [4-6]. For lung and breast cancers, tumor size has been regarded as an important factor in the T category of staging system. However, tumor length is not considered as a prognostic factor for ESCC in this refined esophageal cancer staging system [7, 8]. In this study, ESCC patients who underwent surgery without receiving preoperative chemotherapy or radio-

Accepted for publication Nov 8, 2010. *The first two authors contributed equally to this work, and each should be considered first author. Address correspondence to Dr Wu, Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Rd, Taipei 112, Taiwan; e-mail: [email protected].

© 2011 by The Society of Thoracic Surgeons Published by Elsevier Inc

Patients and Methods Patients The Institutional Review Board of Taipei Veterans General Hospital approved this study and granted a waiver of the inform consent process. Medical records of 688 esophageal cancer patients who underwent esophagectomy at the division of thoracic surgery of Taipei Veterans General Hospital from January 1995 to January 2010 were reviewed retrospectively. Because preoperative radiotherapy or chemotherapy might shrink the tumor length and confound the data of tumor length, patients who received preoperative radiotherapy or chemotherapy (n ⫽ 43) were excluded from this study. Those patients who had histology other than squamous cell carcinoma (n ⫽ 50) and distant metastatic diseases (n ⫽ 13) were also excluded from this study. A total of 582 0003-4975/$36.00 doi:10.1016/j.athoracsur.2010.11.011

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Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taipei; Division of Thoracic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital and Yuh-Ing Junior College of Health Care and Management, Kaohsiung; and Department of Pharmacy, Chia Nan University of Pharmacy & Science, Tainan, Taiwan

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patients with ESCC was included for analysis. All these 582 patients received complete evaluations before surgery including physical examination, biochemistry tests, upper gastrointestinal panendoscopy, bronchoscopy, barium esophagography, chest and abdominal computed tomography scan, abdominal ultrasonography, and radionuclide bone scans. A surgical approach with right thoracotomy, midline laparotomy, and left neck incision combining with mediastinal and intraperitoneal lymph node dissection is the mainstay approach in our hospital. Adjuvant therapy was scheduled for all patients with pathologic T3-4 disease or positive lymph node metastasis. However, there was no uniform guideline and regimen either for adjuvant chemotherapy or radiotherapy after esophagectomy in our hospital during the period of this study.

Pathology Examination The fresh specimen was routinely dissected and measured by surgeons in the operating room immediately after resection of the tumor lesion. Briefly, the esophageal specimen was naturally placed on a measuring table without any stretching assistance. The longitudinal length of each ESCC specimen was measured with a handheld ruler and was recorded in the operation notes. Then the specimens were sent for pathology examination after preservation in 10% neutral buffered formalin. The depth of tumor invasion, grade of differentiation, and lymph node involving status were recorded according to the results of pathologic reports. All patients were staged using the seventh edition of the AJCC TNM staging system [7].

Follow-Up All patients were followed up at our outpatient department every 3 months for the first 2 years after resection, and every 6 months thereafter. The follow-up protocol included medical history, physical examination, and chest computed tomography scan. Upper gastrointestinal panendoscopy and whole body positron emission tomographic scan were arranged if clinically indicated.

Statistical Analysis The survival curve was calculated by the Kaplan-Meier method. The survival time was defined as the interval between date of esophagectomy and date of death or last follow-up. Univariate and multivariate analyses were performed by Cox proportional hazards model using SPSS software (version 12.0; SPSS, Chicago, IL). Clinicopathological factors such as age, sex, surgical approach, reconstruction substitute, route of reconstruction, “T,” “N,” tumor length, histologic grading, tumor location, and adjuvant therapy were included in univariate analyses. The predictors in the seventh edition of the AJCC TNM staging system, age, sex, and tumor length, were selected for multivariate analyses. Statistical analysis was considered to be significant when the probability value was less than 0.05.

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Results The mean follow-up time for all 582 patients was 31.9 months (median 18.0). The 1-, 3-, and 5-year overall survival rates were 70.4%, 37.8%, and 30.0 %, respectively. The median survival was 22 months. The clinicopathologic characteristics of the 582 patients are shown in Table 1. There were 494 patients who underwent triincisional esophageal resection, and they were categorized as one group for analysis. Patients who underwent a transhiatal (n ⫽ 43), Ivor-Lewis (n ⫽ 5), or left-side thoracoabdominal approach (n ⫽ 40) were categorized as another group. The average number of lymph nodes dissected was 24.8 (range 0 to 78) for the triincisional group, and 10.5 (range, 0 to 52) for the others (p ⬍ 0.001). Gastric conduit was used as reconstruction substitute in 562 patients. Colon and free jejunum interposition were performed in 15 and 5 patients, respectively. The 5-year survival rate was assessed against different tumor lengths stratified by every 1-cm increment. The survival rates became worse as tumor length increased. The 5-year survival rates were 77.3%, 48.1%, 38.5%, and 23.3% for tumor lengths of 1 cm, 2 cm, 3 cm, and more than 3 cm, respectively (p ⬍ 0.001). A significant sharp fall was found at the 3-cm cutoff point, and similar 5-year survival rates with tumor length greater than 3 cm was demonstrated (Fig 1). Accordingly, tumor length of 3 cm or less versus more than 3 cm was defined as the cutoff value for further analysis. There was a significant survival difference when patients were stratified into groups using the cutoff value of 3 cm (Fig 2). Patients with tumor length of 3 cm or less (n ⫽ 157) had significantly better median survival (54 versus 17 months) and 5-year survival rate (48.0% versus 23.3%) than did patients with a tumor length greater than 3 cm (p ⬍ 0.001). When tumor length was examined as a continuous variable in the Cox regression model, it still had significant predicting power for overall survival (hazard ratio 1.125; 95% confidence interval: 1.080 to 1.171; p ⬍ 0.001). The type of surgical approach, substitute and route of reconstruction, tumor location, histologic grade as well as with or without adjuvant treatment were not associated with survival in univariate analysis. However, sex (p ⫽ 0.031), T status (p ⬍ 0.001), N status (p ⬍ 0.001), and tumor length (3 cm or less versus more than 3 cm; p ⬍ 0.001) were significantly influenced overall survival in univariate analysis (Table 1). A multivariate Cox regression model was constructed with the incorporation of age, sex, T status, N status, histologic grade, tumor location, and tumor length (3 cm or less versus more than 3 cm). Age, sex, tumor length (3 cm or less versus more than 3 cm), T status, and N status remained as independent prognostic factors (Table 2), but tumor location and histologic grade did not have significant influence on survival in multivariate analysis. For assessing the confounding effect of esophageal tumor length on lymph node status (N0, N1, and N2-3) and depth tumor invasion (T1-2 and T3-4), we further stratified patients into different groups according to the current TNM staging system. As shown in Figure 3A,

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Table 1. Patient Demographic Data and Univariate Survival Analysis

Age, years, median (range) Sex Male Female Surgical approach Triincisional Othersa Substitute organ Stomach Othersb Reconstruction route Retrosternal Posterior mediastinal Subcutaneous Tumor 1 2 3 4 Node 0 1 2 3 Tumor length, mean ⫾ SD Tumor length ⱕ3 cm ⬎3 cm Grade Well differentiated Moderately differentiated Poorly differentiated Tumor location Upper third Middle third Lower third Adjuvant therapy Yes No

Number

5-Year Survival (%)

Median Survival, Months (95% CI)

65.4 (30-88)

30.0

22.0 (18.4–25.6)

541 41

28.7 48.2

22.0 (18.4–25.6) 41.0 (0.1–81.9)

494 88

29.8 31.5

23.0 (18.9–27.1) 18.0 (10.7–25.3)

562 20

29.8 35.2

22.0 (18.4–25.6) 18.0 (0.0–37.5)

465 116 1

30.1 30.2 0

22.0 (18.1–25.9) 21.0 (12.1–29.9) 34

89 128 316 49

56.3 34.6 24.5 8.9

70.0 (47.7–92.3) 27.0 (17.7–36.3) 19.0 (15.3–22.8) 8.0 (4.6–11.4)

p Value — 0.03c

0.800

0.947

0.967

⬍0.001c

⬍0.001c 264 160 99 59 4.8 ⫾ 2.3

45.5 23.9 10.1 5.7

39.0 (21.6–56.4) 22.0 (18.0–26.1) 14.0 (11.8–16.2) 11.0 (8.3–13.7)

157 425

48.0 23.3

54.0 (28.4–79.6) 17.0 (14.5–19.5)

134 381 67

25.9 31.5 29.9

19.0 (14.0–24.0) 26.0 (20.2–31.9) 22.0 (16.3–27.7)

77 340 165

29.0 31.2 28.3

22.0 (9.1–34.9) 22.0 (16.2–27.8) 23.0 (17.0–29.1)

138 444

30.3 30.0

22.0 (12.8–31.2) 22.0 (18.1–25.9)

⬍0.001c ⬍0.001c

0.460

0.680

0.988

Surgical approaches included transhiatal (n ⫽ 43), Ivor-Lewis (n ⫽ 5), or left-side thoracoabdominal incision (n ⫽ 40). c A p value less than 0.05 was considered significant. organ included colon (n ⫽ 15) and jejunum (n ⫽ 5).

a

b

Reconstruction substitute

CI ⫽ confidence interval.

tumor length has a significant influence on overall survival in ESCC patients without lymph node involvement (p ⬍ 0.001). The median survival in patients (n ⫽ 109) with tumor length 3 cm or less and N0 status was better than patients (n ⫽ 155) with a tumor length greater than 3 cm and N0 status (median survival was 59.7 versus 35.5 months). However, the 5-year and median survival rates of patients either with tumor lengths 3 cm or less or greater than 3 cm were similar when the nodes were involved. The influence of tumor length on 5-year sur-

vival in patients with positive N1 and N2-3 disease is shown in Figure 3B and C. According to the T status of disease, patients was divided into T1-2 (n ⫽ 217) and T3-4 (n ⫽ 365) groups for analysis. In the group of T1-2 disease, the median survival of patients with tumor length 3 cm or less (n ⫽ 111; median survival 79.0 months) was significantly better than that of patients with tumor length greater than 3 cm (n ⫽ 106; median survival 25 months; p ⬍ 0.001). In the T3-4 group, the median survival of patients with tumor

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Variables

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Table 2. Multivariate Analysis of Overall Survival of 582 Patients With Esophageal Squamous Cell Carcinoma Variables

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Fig 1. Kaplan-Meier survival curves for 582 patients with esophageal squamous cell carcinoma stratified by 1-cm intervals.

length 3 cm or less (n ⫽ 46; median survival 27.0 months) was also better than that of patients with tumor length more than 3 cm (n ⫽ 319; median survival 15 months; p ⫽ 0.029; Fig 4).

Comment The tumor length of ESCC was ever regarded as an important prognostic factor. The length of esophageal tumor less than 5 cm was categorized as T1 status and greater than 5 cm as T2 status by the AJCC TNM staging system in the version of 1983 [9]. However, tumor length was replaced by depth of esophageal wall invasion as a staging factor in the 1987 version of the AJCC TNM staging system based on the esophageal carcinoma registration database of Japan between 1969 and 1980, which demonstrated the depth of tumor invasion as more accurately correlating with 10-year survival of ESCC patients than the superficial extent of the tumor [10, 11]. The recent edition of the AJCC TNM staging system was published in 2009. In this newly published staging system for esophageal cancer, adenocarcinoma and squamous

Fig 2. Kaplan-Meier survival curves for 582 patients stratified by tumor length (3 cm).

Age Sex Male female Pathologic T classification T1 (reference) T2 T3 T4 Pathologic N classification N0 (reference) N1 N2 N3 Tumor location Upper third (reference) Middle third Lower third Differentiation Well (reference) Moderate Poor Pathologic tumor length ⱕ3 cm (reference) ⬎3 cm a

HR

95% Confidence Interval

p value

1.021

1.011–1.030

⬍0.001a

1.000 0.498

0.315–0.786

0.003a

1.000 1.502 1.682 3.743

0.987–2.286 1.133–2.497 2.285–6.131

0.058 0.010a ⬍0.001a

1.000 1.374 2.211 2.718

1.069–1.765 1.653–2.956 1.919–3.849

0.013a ⬍0.001a ⬍0.001a

1.000 0.873 0.822

0.643–1.184 0.590–1.145

0.382 0.247

1.000 0.867 0.722

0.686–1.097 0.512–1.0174

0.234 0.062

1.000 1.394

1.055–1.842

0.020a

A p value ⬍ 0.05 was considered significant.

HR ⫽ hazard ratio.

cell carcinoma are regarded as two different entities and should be staged separately. It also proposes depth of tumor invasion, number of metastatic lymph nodes, histologic grade, and tumor location as independent staging factors for esophageal cancer. However, it does not emphasize the prognostic role of tumor length in ESCC [7, 8]. Tachibana and colleagues [12] retrospectively evaluated 129 patients with ESCC and indicated that tumor length was related to survival but was not an independent prognostic factor on multivariate analysis, findings that were similar to several previously reported results [13-15]. However, Eloubeidi and coworkers [4] analyzed the outcomes of 10,441 esophageal carcinoma patients from the database of the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) study to identify the prognostic factors of survival. Their results demonstrated that tumor length was an important prognostic factor of survival for patients with esophageal carcinoma and the length of 3 cm was the cutoff point for prediction. They suggested that the T status could be suffixed with either an “a” (3 cm or less) or “b” (more than 3 cm) in the revised TNM system. Although the results of the SEER database provided some important

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Fig 3. Kaplan-Meier survival curves stratified by tumor length in (A) N0 patients, (B) N1 patients, and (C) N2-3 patients.

information and evidence, there still were several limitations in this population-based study, such as data for tumor length missed in 50.4% of patients, the tumor length was measured by various methods, different therapeutic modalities were adopted in this database, and the overall survival was poor (the median survival was 1.2 years for patients with localized disease, 0.8 years for regional disease, and 0.3 years for distant metastatic disease). Each one of these limitations would compromise the strength of the evidence, and it would be difficult to draw a convincing conclusion when interpreting the results obtained from such heterogeneous database. Yendamuri and associates [16] also reviewed a database of 209 esophageal cancer patients (179 adenocarcinomas and 30 squamous cell carcinomas) who underwent surgery without receiving preoperative therapy, and concluded that tumor length is an independent predictor of long-term survival for adenocarcinoma but not for squamous cell carcinoma. However, it is hard to reach a comfortable conclusion based on such a small number of patients with squamous cell carcinoma in that study. To minimize the biases resulting from the heter-

ogeneity of data sources, a single institute’s surgical results were reviewed retrospectively, and only ESCC were enrolled for analysis; and tumor longitudinal length was measured by the surgeon immediately after resection of tumor at operation room in our series. From the database of 582 patients with ESCC who underwent surgical resection, our results clearly demonstrated that tumor length can serve as an independent predictor of long-term survival for ESCC patients, and tumor length greater than 3 cm will be a significant poor prognostic factor. Lymph node status has been shown to be a strong independent prognostic factor in patients with esophageal cancer [17-20]. The interaction effect between lymph node status and tumor length is not well established. In this study, we stratified our patients as N0, N1, and N2-3 groups to evaluate the prognostic effect of tumor length. There was no statistical survival difference between tumors 3 cm or less and more than 3 cm in N1 or N2-3 patients. However, the esophageal tumor length has a significant impact on survival of N0 patients (p ⬍ 0.001). Our finding is consistent with the results of previous studies that also indicated tumor length to be more Fig 4. Kaplan-Meier survival curves stratified by tumor length in (A) T1-2 patients and (B) T3-4 patients.

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significant in localized esophageal cancer [4, 16], but is contrary to the result of Khan and coworkers [1], who suggested that tumor length is not a prognostic factor for esophageal cancer patients (p ⫽ 0.861). The difference in the findings might have resulted from different cell types or sample sizes being analyzed. Khan and associates [1] analyzed 219 esophageal cancer patients who underwent curative esophagectomy for N0 disease. In their series, 59.4% of patients had adenocarcinoma and 40.6% of patients had squamous cell carcinoma. However, only squamous cell carcinoma patients were included in our series, and it decreased the influence of cell types. Accordingly, tumor length will be a good predictor in node-negative ESCC, and the tumor behavior might be more aggressive in node-positive ESCC. The depth of tumor wall invasion is also a wellestablished independent prognostic factor for esophageal cancers [2, 4-6]. In our results, tumor length was also a prognostic factor after controlling the factor of depth of invasion. However, its predictive value was both significant for T1-2 lesions (p ⬍ 0.001) and T3-4 lesions (p ⫽ 0.029). Our finding is consistent with the conclusions of Eloubeidi and colleagues [4] and Bolton and associates [6] who demonstrated that esophageal tumor length greater than 3 cm was a risk factor for poorer long-term survival. It might reflect that tumor length would be a significant indicator of more aggressive biologic behavior of ESCC, especially when tumor localized within muscularis propria of the esophageal wall. Therefore, methods used for measuring tumor length will be the most important factor in interpreting predictive effect of tumor length on long-term survival of ESCC patients. Several published reports demonstrated that formalin fixation might cause shrinkage of the tumor specimen [21]. Siu and associates [22] reported that the whole esophagus specimen might shrink to approximately 50% of its actual length after formalin fixation. The standardized measurement of tumor length in our study will decrease the biases resulting from different methods of measurement. In our study, the length of tumor was measured immediately after specimen resection, and it reflected the real length of the tumor. The disparate length between fresh and fixed specimens may cause conflicting results of analyses. Although the sample size was relatively small as compared with the population database [4, 23], our data originated from a single institution, and a significant prognostic effect of tumor length for ESCC patients was demonstrated in our results. However, there still are several limitations to this study, such as its retrospective nature. In addition, ESCC patients with advanced disease or distant metastasis were not surgical candidates and were not enrolled, as this is a surgical series for analysis. Therefore, our results may not be applied comfortably to all patients with ESCC. As tumor length was not routinely documented by preoperative methods, it was not possible to correlate preoperative tumor length measurements with the final pathologic specimen. In conclusion, tumor length more than 3 cm was significantly associated with poor overall survival and

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demonstrated a predictive effect on survival in nodenegative patients based on analyzing the results of 582 ESCC patients who underwent surgical resection as primary treatment. There was no prognostic role of tumor length in advanced ESCC disease, such as metastatic N1-2-3 lesion. The TNM classification system could take the status of tumor length into consideration as a prognostic factor node-negative disease for ESCC in future revised editions. This work was supported by grants from Center of Excellence for Cancer Research at Taipei Veterans General Hospital (DOH99-TD-C-111-007).

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