The seventh edition of the American Joint Committee on Cancer (AJCC) staging system for esophageal cancer was published in January 2010. A database of 4627 patients who underwent esophagectomy without adjuvant therapy either before or after surgery (esophagectomy alone) from 13 institutions was used to develop this new staging system. Unlike the previous staging system, the new AJCC staging system is not based on the anatomical extent (T, N, and M) alone but includes histopathologic type, biological activity (histologic grade), and tumor location. Moreover, a revision of the N-classification from site-dependent to numerically based staging was also established.1 This renders the current AJCC staging system more reliable than previous editions.
The clinicopathologic presentations of esophageal cancer, including histology, tumor location, and age distribution are known to vary widely between patients in Eastern and Western countries.2,3 More than 50% of patients with esophageal cancer are Chinese.4 However, Asian patients constitute only 25.2% (1168/4627) of the database used to elaborate the seventh edition of the AJCC staging system for esophageal cancer. Because squamous cell carcinoma is the most common pathologic type of esophageal cancer in the East, we believe that more data from Chinese patients should be assembled to evaluate the new staging system. This may create a more highly predictive staging system with widespread applicability.
In the current study, we present data from 2011 patients with esophageal squamous cell carcinoma (ESCC) who underwent surgical resection alone from a single cancer center at the southeast of China. The data were used to evaluate the new AJCC staging system for ESCC and to clarify whether it adequately reflects prognosis.
PATIENTS AND METHODS
This study was undertaken at the Cancer Hospital of Shantou University Medical College and was approved by the Ethics Committee of that hospital. Since January 1995, outcome data for all patients with esophageal cancer undergoing surgical resection were collected prospectively and stored in a database by data managers. Patients were followed with a clinical examination every 3 months for the first year, every 6 months for the second year, and every 6–12 months thereafter. Between January 1995 and June 2010, 3375 cases with esophageal cancer were entered into this database. All operations were performed or closely supervised by two senior surgeons (Y.C. and J.Y.). For this study, only the patients with a histopathologic diagnosis of ESCC with no adjuvant treatment either before or after surgery (esophagectomy alone) were evaluated. Tumors were staged according to the seventh edition of the AJCC staging system for ESCC. N-category was also classified by the extent of lymph node (LN) metastasis (N0 = no LN metastasis; N1 = thoracic or abdominal LN metastasis; N2 = thoracic and abdominal LN metastasis).
By means of a left or right thoracotomy, a surgical resection of a transthoracic en bloc esophagectomy with an end-to-side esophagogastric anastomosis was performed. The thoracotomy was usually performed on the left for tumors located below the aortic arch and on the right for tumors located above the aortic arch. One thousand eight hundred and two patients (89.6%) underwent a left thoracotomy, and the remaining 209 underwent a right thoracotomy. The anastomosis was constructed in the neck through a separate cervical incision in 1948 patients (96.9%) and the upper chest in 63 patients. In all patients, a standard abdominal lymphadenectomy (left and right paracardial regions, along the lesser curve and the left gastric artery) and mediastinal lymphadenectomy (subcarinal, left and right bronchial, lower posterior mediastinum, pulmonary ligament, and paraesophageal and thoracic duct) was performed. For patient who underwent a right thoracotomy, the paratracheal, left, and right recurrent laryngeal nerve LNs were also dissected. Cervical lymphadenectomy was not systematically undertaken.
Statistical analysis was performed using SPSS 13.0 software (SPSS Inc., Chicago, IL, USA). Overall survival time was calculated from the date of operation to the date of death or most recent follow-up. Univariate analysis of survival was performed using the Kaplan–Meier method to estimate survival probabilities in patient subgroups and the log-rank test for statistical comparisons. Multivariate analysis was performed to investigate the prognostic factors by the Cox proportional hazard regression model, with the entry factors of gender, age (≤60 versus >60 years), tumor length (≤5 versus >5 cm), histologic grade, R-category, pT category, pN category, pM category, pTNM stage, and the extent of LN metastasis. All statistical tests were performed two sided, and a p value less than 0.05 was considered to be statistically significant.
Three thousand three hundred and seventy-five esophagectiomies for esophageal cancer were performed between January 1995 and June 2010. Of these, 3181 were histopathologically diagnosed as ESCC. Of these histologically confirmed diagnoses, 2047 did not receive adjuvant chemotherapy or radiotherapy either before or after surgery (esophagectomy alone). Thirty-six patients had to be excluded because of the lack of follow-up data, leaving a study group of 2011 patients (Fig. 1).
There were 1456 men and 555 women with a median age of 55 years (range, 30–82 years). The primary lesions were most often found in the middle third of the thoracic esophagus and had a median length of 5.0 cm (0.5–15.0 cm). An R0 resection (complete tumor resection) was achieved in 1865 patients (92.7%), R1 (microscopically positive margins) in 83 patients (4.1%), and R2 (gross positive residual margins or M1 disease) in 63 patients (3.1%). The overall postoperative 30-day mortality was 1.2% (24/2011). Hospital mortality rate was 1.5% (30/2011).
LN metastases were found in 875 patients (43.5%). A mean of 12.1 LNs (range, 4–44) was dissected from each specimen with a mean number of histologically positive LNs of 1.3.
Follow-up was continued up to June 2011 or until death if this occurred earlier. The mean follow-up was 49.6 months (range, 1–185 months). Seventy-two patients were lost to follow-up (3.6%). The 1-, 3-, and 5-year overall survival rates were 83.5, 57.4, and 47.4%, respectively, with a median survival time of 51.0 months (95% confidence interval: 43.8–58.2).
The distribution of the tumors according to the clinicopathologic characteristics and tumor stage of the seventh edition of the AJCC staging system for ESCC is shown in Tables 1 and 2. The variables related to survival were gender, age, tumor length, histologic grade, R-category, pT category, pN category, pM category, pTNM stage, and extent of LN metastasis (p < 0.05). Tumor location did not influence survival (p = 0.723). In a separate subgroup analysis, the survival differences were not distinctive for the pN2 versus the pN3 category (p = 0.159; Fig. 2A) and stages IA versus IB (p = 0.922).
The pT1N0M0 cancers were subdivided into two groups by histologic grade in the new staging system: pT1N0M0G1 for stage IA and pT1N0M0G2–3 for stage IB. However, prognostic stratification could not be reproduced in our patient cohort. No difference in survival was noted between patients with pT1N0M0G1 and pT1N0M0G2–3 (p = 0.482; Fig. 3A). To find a distinctive classification, we subdivided pT1N0M0 cancers according to tumor location and depth of infiltration. Tumor location did not influence survival in patients with pT1N0M0 cancers (p = 0.561; Fig. 3B). But significant differences were observed with subdivisions by depth of infiltration. Infiltration in the series was defined as limited to the mucosa (pT1a) tumors versus infiltration of the submucosa (pT1b). Patients with pT1aN0M0 had a significantly better outcome than that with pT1bN0M0 (P=0.010; Fig. 3C). When modified, the subdivisions of stage I patients in our cohort according to our findings: stage IA (pT1aN0M0) and stage IB (pT1bN0M0, pT2-3N0M0G1 with tumor locating at the lower third esophagus), the survival difference was also distinctive for stage IA versus IB (p = 0.047). It would seem from the findings from our cohort that subdivisions by depth of infiltration rather than histologic grade for pT1N0M0 cancers may better represent survival advantage.
In a recent study, Yang et al.2 suggested that the nodal categories for Chinese population with ESCC should be more accurately classified into four groups: N0 (no positive LN), N1 (1 positive LN), N2 (2–3 positive LNs), and N3 (≥4 positive LNs). When classifying our patients by these modified nodal categories, the survival differences were distinctive (p < 0.001), and in a subgroup analysis, a statistically significant difference in survival was also found in pN2 versus pN3 category (p = 0.003; Fig. 2B). We also found that classification of N-category according to the extent of LN metastasis was effective in predicting survival in our study (p < 0.001; Fig. 2C).
To identify independent prognostic factors predicting survival after surgery for cancer, Cox regression analysis was performed. The results are presented in Table 3. Age, histologic grade, R-category, pT category, pN category, pM category, pTNM stage, and extent of LN metastasis were independent prognostic factors (p < 0.05). Gender and tumor length were not significantly correlated with survival (p > 0.05).
We report one of the largest ever single-center patient cohorts undergoing surgical resection alone for ESCC to date and evaluate the efficacy of the seventh edition of the AJCC staging system for ESCC. The identification of age, histologic grade, R-category, and AJCC stage as independent prognostic factors in our patient cohort support the findings of previous reports.1,5–8
The goal of a staging system is to have broad predictive power. Previous stage groupings of esophageal cancer were based on a simple, orderly arrangement of increasing anatomical T, then N, and then M classification. These groupings were not consistent with data or cancer biology. At the request of the AJCC, worldwide data were assembled to develop the seventh edition of the staging system for esophageal cancer. Histopathologic cell type, biological activity (histologic grade), and tumor location were added for stage grouping in this new system. Moreover, the new staging system presented a great improvement over previous editions for N-staging by grouping patients according to different numbers of metastatic LNs. But our data do not support the importance of grouping by location as performed in the AJCC staging system. Tumor location was not significantly correlated with survival in our study population.
The number of metastatic LNs was one of the most important independent prognostic factors for patients with esophageal cancer after curative resection.2 Before the seventh edition of the AJCC staging system for esophageal cancer was developed, many studies had examined the relationship between the number of positive LNs and overall survival6,9–17 and tried to obtain an optimal cutoff point. Wijnhoven et al.6 used a special statistical method to determine the optimal cutoff points for the number of positive LNs. In their study, they subdivided pN-stage into three groups based on the number of positive LNs (0, 1–2, and ≥3 nodes positive). Mariette et al.16 adopted a different cutoff of the number of positive LNs (0, 1–4, and >4 nodes positive). Bollschweiler et al.13 found an optimal cutoff point between patients with one to five involved LNs and patients with greater than five LN metastases. Although they all revealed significant differences in prognosis between different groups, the small number of patients in their studies was a hindrance to detailed analysis.
A database of 4627 esophagectomy patients from 13 institutions was used to develop the seventh edition of the AJCC staging system. The N-classification was divided into four groups: N0 (no positive LN), N1 (1–2 positive LNs), N2 (3–6 positive LNs), and N3 (≥7 positive LNs). The large sample size provided sufficient power to detect the relatively small survival difference between groups, making it superior to previous studies.
However, two recent studies from Chinese populations with ESCC suggested that there were no differences in survival between pN2 and pN3 patients,2,18 and we had achieved the same result in our study. Yang et al.2 suggested that the nodal categories for Chinese population with ESCC should be more accurately classified into four groups: N0 (no positive LN), N1 (1 positive LN), N2 (2–3 positive LNs), and N3 (≥4 positive LNs). Our data supported these modified nodal categories. All of these data were assembled from a Chinese population with ESCC. The reasons for the difference in survival factors between Chinese patients and patients from the AJCC require further study. We suggest that more data from other institutions should be assembled to examine this finding.
All of our patients underwent two-field lymphadenectomy. The N-category was also classified by the extent of LN metastasis in our study: N0 = no LN metastasis, N1 = one-field LN metastasis (chest or abdomen), and N2 = two-field LN metastasis (chest and abdomen). Significant differences in survival were observed between different groups. Two-field LN metastases was a predictor of poor survival in patients with ESCC. The classification of N-category according to the extent of LN metastasis was easy and also effective in predicting survival in our study. But whether it is superior to the existing staging system needs further studies.
In the new AJCC staging system, pT1N0M0 cancers were subdivided into two groups by histologic grade: pT1N0M0G1 to stage IA and pT1N0M0G2–3 to stages IB. We, however, did not note a significant difference in survival between these two groups. On the other hand, our data showed that patients with mucosal (pT1a) tumors had a significantly better outcome than tumors infiltrating the submucosa (pT1b) (5-year survival rate: 91.9 versus 67.2%). This could be due to the different risk of LN metastases in pT1a and pT1b tumors (1.8 versus 17.5%). Moreover, subdivisions of pT1N0M0 cancers according to depth of infiltration had a significant impact on survival with pT1aN0M0 tumors having a significantly better outcome than those with pT1bN0M0. This finding is similar to those of many previous reports.6,8,10,19,20 It seems that subclassification of pT1N0M0 cancers by depth of infiltration may correlate better with the survival advantage of ESCC than histologic grade.
Finally, our data did not support the AJCC stage grouping adding tumor location. Tumor location was not significantly correlated with survival in our study population (p = 0.732). This result is similar to the report of Gertler et al.8
Our study has some limitations. First, the relatively small patient numbers in some subgroups may limit statistical power, such as the subgroup analysis of the pN2 versus pN3 categories. Second, it is a single-institution, retrospective study. It is difficult to establish an identical cutoff point for positive LNs in different research centers because of different surgical procedures (transhiatal, two- or three-field lymphadenectomy) in each center or the variant numbers of LNs resected from each patient. A good staging system should have a widespread applicability. It seems reasonable to believe that a multi-institutional collaborative study with a large cohort could achieve a more convincing result. Third, the number of LNs resected from each patient in our study is limited (mean: 12.1 per case). Most of our patients underwent a left thoracotomy. The common hepatic nodes, celiac nodes, and upper right mediastinal nodes were difficult to remove through this operative route. Increasing the extent of lymphadenectomy could provide more accurate pathologic N-staging. However, the extent of lymphadenectomy should be balanced against the risk of complications. Current criteria recommend taking as many LNs as possible. Schwarz and Smith21 used multivariable proportional hazard analysis of the Surveillance, Epidemiology and End-Results data of 5620 esophagectomies and recommended resecting at least 13 LNs. Peyre et al.22 used logistic and Cox regression analysis of an international database of 2303 esophagectomies and recommended that a minimum of 23 LNs should be removed to maximize the survival benefit. Rizk et al.23 used Worldwide Esophageal Cancer Collaboration data to define the optimum lymphadenectomy and recommended that to maximize 5-year survival, a minimum of 10 nodes should be resected for T1 cancer, 20 nodes for T2 cancer, and 30 or more nodes for T3/T4 cancers. Nonetheless, the extent of lymphadenectomy and its effect on improving survival are still debated.
In conclusion, the seventh edition of the AJCC staging system is appropriate for ESCC with an acceptable predictive capability. However, tumor location is not significantly correlated with survival in our study, and the subdivisions of pT1N0M0 cancers and the N-classification may need to be modified. Further studies are required to confirm these results.
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Cancer staging; Esophageal squamous cell carcinoma; Prognosis; Survival