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Original Articles: General Thoracic

Prognostic Variables in Thoracic Esophageal Squamous Cell Carcinoma

^a Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
^b Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan
^c Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan
^d Division of Thoracic Surgery, Department of Surgery, Keelung Hospital, Department of Health, Executive Yuan, Keelung, Taiwan
^e Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
^f Department of Chest, Taipei Veterans General Hospital, Taipei, Taiwan
^g Division of Surgical Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
^h Center for General Education, Kainan University, Taoyuan, Taiwan
ⁱ Division of Thoracic Surgery, Department of Surgery, En Chu Kong Hospital, Taipei, Taiwan

Accepted for publication November 19, 2008.

^_* Address correspondence to Dr Hsu, Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Rd, Shih-Pai, Taipei, 112, Taiwan (Email: whhsu{at}vghtpe.gov.tw).

	Abstract

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 
Background: Thoracic esophageal squamous cell carcinoma (TESCC) is an aggressive malignancy with a poor prognosis. The current American Joint Committee on Cancer (AJCC) TNM cancer staging system focusing on the effect of regional (N1) and nonregional lymph node (M1a and M1b) metastasis may need reappraisal. We investigated the role of the number of dissected and positive nodes in TESCC patients.

Methods: A total of 109 TESCC patients (97 men; mean age of 62.3 years) who underwent surgical resection were retrospectively analyzed. The current AJCC TNM system and other lymph node classifications were used to subgroup these patients and analyze survival differences. Previously reported prognostic factors were evaluated.

Results: Patients with positive lymph node metastasis had a poor prognosis (p < 0.001). There was a significant difference in survival among the 67 node-positive patients subdivided into subgroups with 1 to 3 and 4 or more positive nodes (p = 0.004). Multivariable Cox proportional hazard regression analysis identified four independent prognostic factors: difficulty in swallowing (p = 0.024), cigarette smoking (p = 0.003), number of positive lymph nodes (0, 1 to 3, and 4; p < 0.001), and gastric cardia invasion (p = 0.012). Total dissection of at least 20 lymph nodes was the minimal requirement to achieve accurate nodal staging.

Conclusions: Dissection of more than 20 lymph nodes is mandatory in TESCC patients to achieve accurate staging. Positive lymph node metastasis of 4 or higher is a significant independent prognostic factor.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 
Thoracic esophageal squamous cell carcinoma (TESCC) is one of the most common and aggressive cancers in Asia, especially in southern China [1, 2], Hong Kong [3], and Taiwan [4]. Surgery remains the mainstay of treatment for TESCC patients if there are no specific contraindications [5]. Despite advances in public health care and the introduction of National Health Insurance in Taiwan in 1995, the reported 5-year survival rate remains about 30% among patients who undergo surgical intervention [6–9]. Because of the unfavorable outcome of patients with TESCC, a search for useful prognostic factors is clinically important.

The current American Joint Committee on Cancer (AJCC) surgical-pathologic TNM staging system described in the sixth edition of the AJCC Cancer Staging Manual [10] has been adopted to classify patients with TESCC after surgical resection. The role of N status in predicting long-term survival of patients with TESCC has been reported. However, the optimal classification of N status remains inconclusive [6, 11–14]. To compare and investigate the effect of different classifications on N status is of clinical relevance and importance.

In this retrospective study, we compared and evaluated the usefulness of different N status classifications in predicting clinical outcomes. The number of lymph nodes needed to be dissected for adequate N staging was also investigated. This issue is relevant to both thoracic surgeons and clinical oncologists.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 
Patients
This retrospective study analyzed 109 patients diagnosed with TESCC who underwent surgical resection as the primary modality of treatment at Taipei Veterans General Hospital and Keelung Hospital between January 2000 and December 2004. Patients had resectable TESCC and were without obvious distant organ metastasis on preoperative assessment. Postoperative adjuvant radiotherapy or chemotherapy, or both, were scheduled if clinically indicated. The Institutional Review Board of Taipei Veterans General Hospital approved the study and informed consent was waived.

The preoperative workup included a chest roentgenogram, an upper gastrointestinal series and endoscopic examination, a thoracic computed tomography (CT) scan from the lower neck to the upper abdomen, a whole body bone scan, a complete blood count with cell differential, a routine urine test, blood biochemistries, pulmonary function testing, and cardiac ejection fraction plus wall motion for accessing each patient's general and oncologic status. Abdominal ultrasound or CT scanning of the brain was performed if clinically indicated. The patients underwent surgical resection after completing the preoperative evaluation and providing written consent.

The surgical modalities included:

1 standard right-side thoracotomy for transthoracic subtotal esophagectomy with residual cervical esophagus for further anastomosis and radical lymph node dissection along the periesophageal region, including paratracheal, hilar, subcarinal, paraesophageal, and inferior pulmonary ligament lymph nodes (grouped as thoracic lymph nodes [N_T]);

2 exploratory laparotomy for gastric tube reconstruction after gastric cardiectomy and dissection of the abdominal lymph nodes along the left gastric artery to the main celiac trunk (grouped as abdominal lymph nodes [N_A]); and

3 left cervical oblique incision for esophagogastric anastomosis and lymph node sampling if clinically suspected (grouped as cervical lymph nodes [N_C]).

According to the current AJCC classification, the N_C, N_T, and N_A nodes belong to the regional nodes of the cervical, thoracic, and abdominal esophagus, including the gastroesophageal junction, respectively [10].

Tumor Location and AJCC TNM Classification
In the AJCC Cancer Staging Manual [10], the thoracic esophagus is divided into upper thoracic (T-u, approximately 20 to 24 cm from the upper incisor teeth), middle thoracic (T-m, approximately 24 to 32 cm from the upper incisor teeth), and lower thoracic (T-l, approximately 32 to 40 cm from the upper incisor teeth) portions by two landmarks, the tracheal bifurcation, which is approximately 24 cm from the upper incisor teeth, and the inferior pulmonary vein, which is approximately 32 cm from the upper incisor teeth. The main tumor location is classified according to the portion of the esophagus in which it is located. If the tumor crosses two portions, it is classified according to the predominant portion involved by the tumor [10].

The T, N, and M status is defined and named according to the criteria described in the AJCC Manual [10]. T status denotes the depth of tumor invasion through the esophageal wall, as follows: lamina propria/submucosa invasion (T1), muscularis propria invasion (T2), adventitia invasion (T3), and paraesophageal soft tissue/adjacent structures invasion (T4). Lymph nodes harvested from the N_C, N_T, and N_A fields are classified into regional and nonregional lymph nodes with reference to the location of the primary TESCC tumor, and they are designed in the N status (regional lymph nodes) and M status (nonregional lymph nodes) separately. Nonregional lymph nodes are further divided into M1a and M1b lymph nodes with respect to the location of the primary TESCC. Briefly, the lymph nodes are classified as follows:

1 for any intrathoracic lesions (T-u, T-m, and T-l), the N_T are defined as regional lymph nodes, and N_A and N_C are defined as nonregional lymph nodes (M1a or M1b lymph nodes);

2 for a T-u lesion, the N_C are defined as M1a lymph nodes, and the N_A are defined as M1b lymph nodes;

3 for a T-l lesion, the N_A are defined as M1a lymph nodes, and the N_C are defined as M1b lymph nodes; and

4 for a T-m lesion, both N_A and N_C are defined as M1b lymph nodes, and no M1a lymph nodes are defined.

The current N designation in the AJCC classification is focused on the status of the regional lymph nodes only, and the nonregional lymph nodes are not included. When regional lymph nodes are positive for metastasis, N1 status is assigned. In contrast, if the regional lymph nodes are negative for metastasis, N0 status is assigned.

The current M status in the AJCC classification is focused on the status of the nonregional lymph nodes and distant organs. M0 status indicates no detectable metastasis to the nonregional lymph nodes and distant organs. M1 status is indicative of positive nonregional lymph nodes (M1a/M1b lymph node metastasis) or distant organ metastasis. M1a lymph nodes that are positive for metastasis are defined as M1a status in stage IVa. M1b lymph nodes or distant organs that are positive for metastasis are defined as M1b status in stage IVb.

When such definitions are used for lymph nodes classification, TESCC patients classified as M1a or M1b status could be either N0 or N1 status. Thus, T2 N0 M1a in stage IVa indicates negative regional lymph node metastasis but positive nonregional M1a lymph node metastasis, whereas T2 N1 M1a in stage IVa indicates both regional and nonregional M1a lymph nodes positive for metastasis. In the current AJCC TNM classification, both T2 N1 M1a and T2 N0 M1a belong to stage IVa due to M1a status, regardless of the presence or absence of positive regional lymph node metastasis (N0 or N1 status).

Lymph Node Classification
Patients with positive lymph node metastasis in any fields (N_C, N_T, or N_A) are classified as N-positive (+). Patients without lymph node metastasis are classified as N-negative (–). Those N+ patients are subgrouped to N1 status (positive for N1 lymph node metastasis but negative for M1a and M1b lymph node metastasis), M1a status (undetermined N status and positive for M1a lymph node metastasis, but negative for M1b lymph node metastasis), and M1b status (undetermined N and M1a status, but positive for M1b lymph node metastasis), according to the current AJCC definition. The N+ patients are further subgrouped as follows:

1 patients with regional lymph nodes positive for metastasis (ie, N1 M0 in AJCC), positive nonregional lymph node metastasis (ie, N0 M1a, N0 M1b, or N0 M1a M1b in AJCC), and both positive regional and nonregional lymph node metastasis (ie, N1 M1a, N1 M1b, or N1 M1a M1b in AJCC);

2 fields with lymph nodes positive for metastasis (1, 2, or 3 fields; any combination of N_C, N_T, or N_A); and

3 number of nodes positive for metastasis (1 to 3 and 4).

Prognostic Factors
All the potential and reported prognostic factors were recorded for analysis, including demographic data, swallowing conditions, cigarette smoking or alcoholic consumption, and tumor characteristics. Concurrently, the different classifications for positive lymph node metastasis, as mentioned above, compared with the AJCC lymph node classification were evaluated and discussed.

All the clinical data were reviewed and recorded using the computerized database and special charts by Dr Lin. All of the patients were monitored until December 2006.

Statistical Analysis
The continuous variables between groups were compared using a t test, Mann-Whitey U test, or analysis of variance and Kruskal-Wallis H test when appropriate. Categoric variables between groups were compared using the ² test, Fisher exact test, or linear-by-linear association when appropriate. The survival intervals (overall survivals) were calculated from the date of operation to the date of death or last follow-up in December 2006. Patient survival curves were calculated and plotted by the Kaplan-Meier method. The log-rank test was used to compare the survival difference among groups within each categoric variable. The possible prognostic factors associated with survival probability at a significance level of p 0.20 were considered in a multivariable Cox proportional hazard regression analysis. A value of p < 0.05 was considered significant. Statistical analysis was performed with SPSS 12.0 software (SPSS Inc, Chicago, Ill).

	Results

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 
Clinical Data
Between January 2000 and December 2004, 109 TESCC patients (97 men and 12 women), with a mean age of 62.3 years, were eligible for analysis. Of these, 82 (75.2%) patients smoked cigarettes, and 75 (68.8%) drank alcohol. Regarding tumor location, 13 (11.9%) were in T-u, 55 (51.5%) were in T-m, and 41 (37.6%) were in T-l, with mean distances from the upper incisor teeth of 21.6, 27.9, and 34.3 cm, respectively. According to the AJCC staging system, 8 patients (7.3%) were stage I, 33 (30.3%) were stage II, 26 (23.9%) were stage III, and 42 (38.5%) were stage IV due to nonregional lymph node metastasis. The overall mean and median survival periods were 34.3 and 22.9 months, respectively (Table 1). The 1-, 2-, 3-, and 5-year survival rates were 72.2%, 49.6%, 36.6%, and 31.5%, respectively.

View larger version (27K): [in this window] [in a new window]   Fig 1. Illustrated are Kaplan-Meier survival curves, hazard ratio (HR), including 95% confidence interval (CI), patients at risk, and p values of the four independent factors related prognostic outcomes in thoracic esophageal squamous cell carcinoma patients, including (A) difficulty in swallowing, (B) cigarette smoking, (C) number of positive lymph node metastasis exceeding 4 and (D) gastric cardia invasion.

	Comment

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 
The pattern of the pathologic types of esophageal cancer between Western and Asian countries, especially China, Korea, Japan, and Taiwan, is quite different. Adenocarcinoma of the lower esophagus and the gastroesophageal junction, including the proximal gastric cardia portion, is prevalent in the West. In contrast, SCC of the thoracic esophagus is more prevalent in Asia [15]. Most TESCC patients experience difficulty in swallowing in the advanced stage of the disease. Because the tube and muscular structure of the esophagus can accommodate a gradually enlarging tumor mass, it may easily be neglected as ESCC. As a result, the symptom of dysphagia is considered to be an ominous sign of poor outcome in TESCC [16]. In this study, difficulty in swallowing appeared to be related to a shorter survival period and regarded as an important independent poor prognostic factor (Table 4, Fig 1A). To verify the prognostic role of swallowing difficulty in TESCC, we further correlated the relationship to tumor size and pathologic T status. The mean tumor size for the 89 TESCC patients with symptoms of swallowing difficulty was 4.4 ± 1.5 cm, which was significantly larger than the mean size of 3.6 ± 1.8 cm in the 20 patients without symptoms of swallowing difficulty (p = 0.042, Mann-Whitney U test). The incidence of swallowing difficulty was 33.3% (3 of 9) in T1 lesions, 77.3% (17 of 22) in T2 lesions, 85.7% (36 of 42) in T3 lesions, and 91.7% (33 of 36) in T4 lesions of TESCC patients. There was a significant trend toward swallowing difficulty with advanced T status (p < 0.001, linear-by-linear association test). As a result, it is reasonable to explain why swallowing difficulty is an independent factor related to poor outcome in TESCC patients. Cigarette smoking is reported to be a risk factor for the development of TESCC and is associated with poor long-term prognosis in several studies [4, 17, 18]. Our results are in agreement with these reports and revealed that cigarette smoking is an independent factor related to poor outcome (Table 4, Fig 1B). Thus, quitting cigarette smoking can be beneficial for preventing the occurrence and development of esophageal cancer.

Clinically, AJCC TNM staging system is widely accepted for staging of ESCC patients and tailoring optimal therapies. In this study, N– patients survived longer than N+ patients (p < 0.001, Table 2). However, the survival periods of N+ patients vary widely, and further lymph node classification for these N+ patients is mandatory. Several types of classification of lymph node metastasis for human cancers have been described in AJCC cancer staging systems, some focused on the metastasis in regional/nonregional lymph nodes, and some focused on the number of lymph node metastasis to predict clinical outcomes [10].

The definitions of positive N1, positive M1a, and positive M1b lymph node metastasis (N1, M1a, and M1b status) in TESCC are similar to the positive N1 (ipsilateral), positive N2 (junctional and midline), and positive N3 (contralateral) lymph node metastasis (N1, N2, and N3 status) in nonsmall cell lung cancer relative to the location of the primary tumor, emphasizing the poor outcome when distant nonregional lymph node metastasis is detected. Such groupings are different from that of gastric and colon cancers over the digestive system, and they focus on the minimal requirements of total lymph node dissection and the number of positive node metastasis (0, 1 to 6, 7 to 15, and >15 for gastric cancer; 0, 1 to 3, and 4 for colon cancer) for distinguishing survival differences. It should be emphasized that poor prognosis is related to the number of lymph node metastases [10]. Thus, the roles of regional/nonregional lymph node metastasis or number of positive lymph node metastasis in predicting TESCC survival was studied.

Our series found no significant survival differences among TESCC patients grouped according to N1, M1a, and M1b status (Table 3, p = 0.8954). The 14 patients with positive nonregional lymph node metastasis only (without regional lymph node metastasis, ie, N0 M1a or N0 M1b in AJCC stage IV) had better survival than the 25 patients with positive regional lymph node metastasis only (without nonregional lymph node metastasis, N1 M0 in AJCC, stage < IV). The worst survival was noted in the 28 patients who had both positive regional and nonregional lymph node metastasis (N1 M1a, N1 M1b, and N1 M1a M1b in AJCC stage IV; p = 0.0621, log-rank test, Table 3). The results are different from the current AJCC staging systems, and the roles of N1, M1a, and M1b status needs to be reappraised. Under the current AJCC classification, several N+ TESCC patients would be upstaged to stage IV due to nonregional M1a or M1b lymph node involvement rather than distant organ metastasis. In particular, those with TESCC in the middle thoracic esophagus would frequently be in stage IVb if they had cervical or abdominal lymph node metastasis.

In our preliminary results, 42 N+ patients were in stage IV due to nonregional lymph nodes (regardless of the regional lymph node status) after pathologic confirmation (19 positive for M1a lymph nodes in M1a status and 23 for M1b lymph node metastasis in M1b status). As described in our series, TESCC patients with positive nonregional lymph node metastasis only (N0 M1a and N0 M1b, in stage IV, AJCC) had better survival than the patients with positive regional and nonregional lymph node metastasis (N1 Ma, N1 M1b, and N1 M1a M1b in stage IV, AJCC), but all were classified as stage IV in the present classification (Table 3). Thus, the role of nonregional node involvement needs to be reappraised in further studies.

The significance of the number of positive lymph node metastasis in TESCC was recently raised, but the optimal cutoff value of the positive number is controversial [6, 11–13, 19–21]. In our study, 67 N+ patients were divided into different subgroups to determine the most important factor of adverse survival effect (Table 3). Positive lymph node metastasis of 4 or more appeared to be an optimal cutoff value to distinguish survival differences in those N+ patients other than the current AJCC N classification. In Table 2, current AJCC T, M, and cancer stage are significant prognostic factors related to survival outcomes and can predict survival separately with clinical significances. Intriguingly and interestingly, T and M and cancer stage lose their differentiating powers after incorporating N status grouped according to the number of positive lymph node metastasis (0, 1 to 3, 4) in the Cox regression model with stepwise analysis (Table 4). The number of positive lymph node metastasis was one of the independent prognostic factors (p = 0.001; Table 4, Fig 1C).

To further discuss whether the current AJCC TNM and cancer staging system lose their predictive power after comparing the N status grouped according to the number of positive lymph node metastasis, we summarized their relationships (Table 5). The number of positive lymph node metastasis increased stepwise with advanced tumor stage based on the AJCC TNM and cancer staging system. In other words, the AJCC TNM and cancer stage can be reflected and replaced simply by the number of the positive lymph nodes, if adequate lymph node dissection was done. The findings were consistent with the results of previous studies [22, 23]. Taken together, the number of positive lymph node metastasis divided by 0, 1 to 3, and 4 or more may be an important pathologic staging factor to predict the outcome of TESCC.

Another problem is the number of lymph nodes that is required to be dissected (ie, adequate lymph node dissection for staging). Undoubtedly, we have a higher probability of detecting positive lymph nodes if we perform more extensive lymph node dissection. Our results indicate that the detection rate increases with T status, and thus the requirement of total dissected lymph nodes to detect a positive lymph node decreased (Table 6, upper portion). Considering T2 lesions, we expect to find 1 positive lymph node metastasis in every 20 nodes dissected in patients with T2 lesions. When 20 is used as the cutoff value of the minimal requirement for total lymph node dissection, the number of positive lymph node metastasis in patients undergoing total dissection exceeding 20 are more than those receiving total dissection of 20 or fewer nodes among patients with T2, T3, and T4 lesions. Owing to the small sample size of the T1 lesion, whether 20 nodes are sufficient to detect positive lymph node metastasis accurately remains to be determined by a larger prospective study. Similar results were reported by Rizk and colleagues [19], who suggested that 18 lymph nodes is the minimum required to achieve accurate staging.

The fourth independent factor to poor prognosis identified in our study was gastric cardia invasion, as evidenced by pathologic diagnosis. Although the resection margins of the gastric cardia during cardiectomy of all 109 TESCC patients were free of tumor invasion, 10 were found to have TESCC cancer nests in the gastric portion from the esophagus invading through the esophageal junction to the gastric cardia. Of these 10 patients, 1 had a primary lesion located in T-u, 3 in T-m, and 6 in T-l. The findings indicated that TESCC invades not only vertically (depth of tumor invasion = T status), but also horizontally through the esophageal junction to the gastric cardia portion. Eight of the 10 patients had positive N_T lymph node metastasis (regional nodes), 7 had positive N_A lymph node metastasis (nonregional nodes), and 6 had both positive N_T and N_A lymph node metastasis. It is plausible that once primary TESCC invades the gastric cardia, the incidence of concurrent positive N1 and M1 lymph node metastasis are high. Accordingly, these patients have shorter survival after treatment. Because of the limitation of number of patients, further studies with larger patient numbers are needed.

In conclusion, this study identified four independent factors for a poor TESCC prognosis, including difficulty in swallowing, cigarette smoking, more positive lymph node metastasis, and gastric cardia invasion. The number of positive lymph node metastasis (0, 1–3, and 4) has considerable value in predicting the outcome of patients after surgical intervention and improving the usefulness of the AJCC TNM staging system. To achieve an optimal detection rate for positive lymph node metastasis, adequate dissection of at least 20 lymph nodes is recommended.

	Acknowledgments

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 
We would like to express our sincere appreciation to Dr Hui-Chen Lin for her assistance with statistical analyses.

	Footnotes

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 
^_* Drs Hsu and Chang contributed equally in this work.

	References

Top Abstract Introduction Patients and Methods Results Comment Footnotes Acknowledgments References

 

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