Prognostic Variables in Thoracic Esophageal Squamous Cell Carcinoma

GENERAL THORACIC

Prognostic Variables in Thoracic Esophageal Squamous Cell Carcinoma Chen-Sung Lin, MD, Shi-Chuan Chang, MD, PhD,* Yau-Huei Wei, PhD, Teh-Ying Chou, MD, PhD, Yu-Chung Wu, MD, Hui-Chen Lin, PhD, Liang-Shun Wang, MD, and Wen-Hu Hsu, MD* Institutes of Clinical Medicine and Emergency and Critical Care Medicine, and Department of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Division of Thoracic Surgery, Department of Surgery, Keelung Hospital, Department of Health, Executive Yuan, Keelung, Division of Thoracic Surgery, Department of Surgery, Department of Chest, and Division of Surgical Pathology, Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Center for General Education, Kainan University, Taoyuan, and Division of Thoracic Surgery, Department of Surgery, En Chu Kong Hospital, Taipei, Taiwan

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 ⴝ 0.004). Multivariable Cox proportional hazard regression analysis identified four independent prognostic factors: difficulty in swallowing (p ⴝ 0.024), cigarette smoking (p ⴝ 0.003), number of positive lymph nodes (0, 1 to 3, and >4; p < 0.001), and gastric cardia invasion (p ⴝ 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. (Ann Thorac Surg 2009;87:1056 – 65) © 2009 by The Society of Thoracic Surgeons

T

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.

horacic 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

Accepted for publication Nov 19, 2008. *Drs Hsu and Chang contributed equally in this work. 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; e-mail: whhsu@vghtpe. gov.tw.

© 2009 by The Society of Thoracic Surgeons Published by Elsevier Inc

Patients and Methods 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. 0003-4975/09/$36.00 doi:10.1016/j.athoracsur.2008.11.051

LIN ET AL THORACIC ESOPHAGEAL SQUAMOUS CELL CANCER

Table 1. The General Characteristics of the 109 Thoracic Esophageal Squamous Cell Carcinoma Patients Demographics Age, years Gender Male Female Cigarette smoking Yes No Alcohol consumption Yes No Tumor location Thoracic-upper Thoracic-middle Thoracic-lower Distance from upper incisor teeth, cm Thoracic-upper Thoracic-middle Thoracic-lower Surgical-pathologic stage (AJCC) I II III IV Survival, months Mean Median AJCC ⫽ American Joint Committee on Cancer; deviation.

Number (%) or Mean ⫾ SD 62.3 ⫾ 12.5

1057

to the main celiac trunk (grouped as abdominal lymph nodes [NA]); and 3. left cervical oblique incision for esophagogastric anastomosis and lymph node sampling if clinically suspected (grouped as cervical lymph nodes [NC]).

97 (89.0) 12 (11.0)

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

82 (75.2) 27 (24.8)

Tumor Location and AJCC TNM Classification

75 (68.8) 34 (31.2) 13 (11.9) 55 (51.5) 41 (37.6) 21.6 ⫾ 1.4 27.9 ⫾ 2.1 34.3 ⫾ 3.4 8 (7.3) 33 (30.3) 26 (23.9) 42 (38.5) 34.3 22.9 SD ⫽ standard

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 [NT]); 2. exploratory laparotomy for gastric tube reconstruction after gastric cardiectomy and dissection of the abdominal lymph nodes along the left gastric artery

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 NC, Nt, and NA 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 NT are defined as regional lymph nodes, and NA and NC are defined as nonregional lymph nodes (M1a or M1b lymph nodes); 2. for a T-u lesion, the NC are defined as M1a lymph nodes, and the NA are defined as M1b lymph nodes; 3. for a T-l lesion, the NA are defined as M1a lymph nodes, and the NC are defined as M1b lymph nodes; and 4. for a T-m lesion, both NA and NC 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.

GENERAL THORACIC

Ann Thorac Surg 2009;87:1056 – 65

GENERAL THORACIC

1058

LIN ET AL THORACIC ESOPHAGEAL SQUAMOUS CELL CANCER

Table 2. The Possible Prognostic Factors Affecting Long-Term Survival Rates Possible Prognostic Factor Gender Male Female Presenting symptoms Difficulty in swallowing Yes No Body weight loss Yes No Special habit Cigarette smoking Yes No Alcohol consumption Yes No Tumor location Thoracic-upper Thoracic-middle Thoracic-lower Pathologic findings Esophageal resection margin invasion Yes No Gastric cardia invasion Yes No T status T1 T2 T3 T4 N status Without LN metastasis With LN metastasis M status M0 M1a M1b Cancer stage (AJCC) I II III IV a

Patient, Mean Survival p No. (95% CI), Months Valuea 0.3928 97 12

33.1 (27.3–39.0) 41.3 (25.3–57.3)

89 20

31.1 (25.1–37.1) 48.0 (36.1–59.9)

33 73

38.4 (27.0–49.8) 32.6 (26.4–38.9)

82 27

30.6 (24.5–36.8) 43.8 (32.3–55.2)

75 34

30.6 (24.5–36.7) 41.3 (30.4–52.1)

0.0209

0.5361

0.0667

Ann Thorac Surg 2009;87:1056 – 65

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).

0.1318

Lymph Node Classification 0.2100

13 55 41

22.2 (10.3–34.2) 37.7 (29.8–45.5) 32.6 (23.4–41.9) 0.0547

16 93

20.6 (10.8–30.4) 36.2 (30.0–42.4)

10 99

10.5 (4.5–16.5) 36.4 (30.5–42.3)

9 22 42 36

50.9 (36.5–65.1) 37.0 (25.0–49.0) 35.9 (27.5–44.2) 26.3 (16.7–35.8)

42 67

47.1 (38.0–56.2) 25.6 (19.4–31.7)

67 19 23

39.1 (32.0–46.2) 27.5 (15.1–39.9) 21.9 (14.0–29.9)

8 33 26 42

54.3 (40.1–68.6) 40.3 (30.0–50.6) 30.8 (20.6–41.0) 26.0 (17.8–34.2)

0.0005

0.0333

0.0003 0.0422

0.0285

Univariable log-rank.

AJCC ⫽ American Joint Committee on Cancer; interval; LN ⫽ lymph node.

CI ⫽ confidence

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

Patients with positive lymph node metastasis in any fields (NC, NT, or NA) 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 NC, NT, or NA); and 3. number of nodes positive for metastasis (1 to 3 and ⱖ4).

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.

LIN ET AL THORACIC ESOPHAGEAL SQUAMOUS CELL CANCER

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 ⱕ 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 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

1059

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.

Prognostic Factors The possible prognostic factors affecting long-term survival were evaluated and compiled in Table 2. Univariable analysis indicated that difficulty in swallowing (p ⫽ 0.0209), cigarette smoking (p ⫽ 0.0667), advanced T status (p ⫽ 0.0333), positive lymph node metastasis (p ⫽ 0.0003), concurrent M lesions (p ⫽ 0.0422), and late cancer stages (p ⫽ 0.0285) tended to be associated with shorter survival periods. Pathologic examinations found atypical cells had invaded cervical esophageal resection margins in 16 patients (5 SCC, 6 carcinoma in situ, and 5 dysplasia), and they had shorter survival periods (p ⫽ 0.0547). Although the resection margins over the gastric cardia portion for all the 109 TESCC patients were free of SCC invasion, 10 patients had gastric cardiac invasion by the main cancer nests from the esophagus through the esophagogastric junction to the gastric cardia portion and thus had a poor prognosis (p ⫽ 0.0005).

Effect of Lymph Node Classifications in TESCC Patients With Positive Lymph Node Metastasis Of the 109 patients, 42 were N⫺ and 67 were N⫹. The 67 N⫹ patients were further grouped according to AJCC

Table 3. Classifications for the 67 Nodal Positive Patients and the Survival Differences after Multivariable Cox Proportional Hazard Regression Analysis Types of Positive LN Classification LN metastasis Regionala Nonregionalb Bothc Fields with positive LN metastasis One (NC, NT, NA) Two (either two of NC, NT, or NA) Three (NA ⫹ NB ⫹ NC) Positive LN metastasis, No. 1–3 (reference) ⱖ4 LN vs 1–3 AJCC classification N1 statusd M1a statuse M1b statusf

Patient, No.

Mean Survival (95% CI), Months

Univariable Log Rank p Value

Multivariable Cox Regression p Value

25 14 28

25.5 (16.4–34.5) 34.6 (22.6–46.6) 18.0 (10.5–25.5)

0.0621

0.178

38 24 5

29.6 (21.9–27.3) 19.2 (10.5–27.9) 11.4 (6.7–16.2)

0.0399

0.222

44 23

31.1 (22.9–39.4) 13.7 (9.0–18.4)

0.0028

0.004

25 19 23

25.5 (16.4–34.5) 27.5 (15.1–39.9) 21.9 (14.0–29.9)

0.8954

HR

95% CI

1.000 2.325

1.316–4.108

a Regional LN metastasis: positive for regional LN metastasis; negative for nonregional LN metastasis, including 25 patients in AJCC N1 b Nonregional LN metastasis indicates positive for nonregional LN metastasis but negative for regional LN metastasis, including 6 patients in M0. c AJCC N0 M1a and 8 in AJCC N0 M1b. Both regional and nonregional LN metastasis indicates positive for both regional and nonregional LN d N1 status included 25 patients with N1 metastasis, including 13 patients in AJCC N1 M1a, 12 in AJCC N1 M1b, and 3 in AJCC N1 M1a M1b. e f M1a status included 6 patients with N0 M1a, and 13 with N1 M1a. M1b status included 8 patients with N0 M1b,12 with N1 M1b, and 3 with M0. N1 M1a M1b.

AJCC ⫽ American Joint Committee on Cancer; CI ⫽ confidence interval; HR ⫽ hazard ratio (the HR of the reference is defined as 1); lymph node; NA ⫽ abdominal LN; NC ⫽ cervical LN; NT ⫽ thoracic LN.

LN ⫽

GENERAL THORACIC

Ann Thorac Surg 2009;87:1056 – 65

GENERAL THORACIC

1060

LIN ET AL THORACIC ESOPHAGEAL SQUAMOUS CELL CANCER

Ann Thorac Surg 2009;87:1056 – 65

and our classification, as described. Univariable analysis indicated metastasis in both regional and nonregional lymph nodes (p ⫽ 0.0621), more fields with positive node metastasis (any combination of NC, NT, or NA, p ⫽ 0.0399), and a greater number of positive lymph node metastasis (1 to 3 and ⱖ4, p ⫽ 0.0028) were associated with poorer prognosis. As listed in Table 3, four or more lymph nodes positive for metastasis had the worse prognosis for survival based on multivariable Cox’s proportional hazard regression analysis, with a hazard ratio (HR) of 2.325 (95% confidence interval [CI], 1.316 to 4.180; p ⫽ 0.004; ⱖ4 vs 1 to 3) when the HR of 1 to 3 lymph node metastasis was defined as 1.

regression analysis (Table 4), the four independent factors related to poorer outcomes were difficulty in swallowing (HR, 2.277; 95% CI, 1.115 to 4.652; p ⫽ 0.024, when the HR of no difficulty in swallowing was defined as 1; Fig 1A), cigarette smoking (HR, 2.472; 95% CI, 1.356 to 4.507; p ⫽ 0.003, when the HR of no cigarette smoking was defined as 1; Fig 1B), number of positive lymph node metastasis of 4 or more (HR, 4.224; 95% CI, 2.128 to 8.385; p ⫽ 0.001, when the relative risk of 0 lymph node metastasis was defined as 1; Fig 1C), and gastric cardia invasion (HR ⫽ 2.865, 95% CI ⫽ 1.265– 6.489, p ⫽ 0.012, when the relative risk of no gastric cardia invasion was defined as 1; Fig 1D).

Independent Prognostic Factors

Number of Positive Lymph Node Metastasis and AJCC TNM Staging Classification

The number of positive lymph node metastasis of 4 or more was the most useful criterion to distinguish prognosis in N⫹ patients, and we compared the effect on survival with the other prognostic factors listed in Table 2. After multivariable Cox proportional hazard

The relationships between the number of positive node metastasis and the AJCC TNM classification are listed in Table 5. The mean number of positive lymph node metastasis increased significantly from T1, T2, and T3 to

Table 4. Possible Independent Prognostic Factors and Relative Risk Cox Regression Prognostic Factor Difficulty in swallowing Yes No (reference) Cigarette smoking Yes No (reference) Pathologic findings Esophageal resection margin invasion Yes No Gastric cardia invasion Yes No (reference) T status (AJCC) T1 T2 T3 T4 N status (positive LN metastasis) 0 (reference) 1–3 vs 0 ⱖ4 vs 0 M status (AJCC) M0 M1a M1b Cancer stage (AJCC) I II III IV AJCC ⫽ American Joint Committee on Cancer;

Patient, No.

p Value

HR

95% CI

2.277 1.000

1.115–4.652

2.472 1.000

1.356–4.507

2.865 1.000

1.265–6.489

0.024 89 20 0.003 82 27 0.152 16 93 0.012 10 99 0.700 9 22 42 36 ⬍0.001 42 44 vs 42 23 vs 42

0.051 ⬍0.001 0.897

1.000 1.744 4.224

0.997–3.050 2.128–8.385

67 19 23 0.339 8 33 26 42 CI ⫽ confidence interval;

HR ⫽ hazard ratio (the HR of the reference is defined as 1).

LIN ET AL THORACIC ESOPHAGEAL SQUAMOUS CELL CANCER

1061

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.

T4 lesions in T status (p ⫽ 0.001); N–, N1, and M1a to M1b conditions in N status (p ⬍ 0.001); M0 and M1a to M1b conditions in M status (p ⬍ 0.001); and stages I, II, and III to IV in cancer stages (p ⬍ 0.001, Kruskal-Wallis test; Table 5, left side). Among the three patient groups divided according to the number of positive lymph node metastasis of 0, 1 to 3, and 4 or more, there was a trend toward metastatic lymph node severity to advanced AJCC T status (p ⬍ 0.001), N status (p ⬍ 0.001), M status (p ⬍ 0.001), and cancer stage (p ⬍ 0.001, linear-by-linear association test; Table 5, right side). The current AJCC

TNM staging system is thoroughly reflected by the number of positive lymph node metastasis.

The Total Number of Dissected Lymph Nodes and the Rate of Detection for Positive Lymph Node Metastasis The 109 patients had a mean total of 21.0 dissected lymph nodes and a mean of 2.3 positive lymph nodes. The mean rate of detection of positive nodes (the number of positive lymph node metastasis/total dissected lymph nodes in each patient) of the 109 patients was 12.8% (1 of 7.8 [12.8%] ⫽ 1/7.8, the probability of finding a positive

GENERAL THORACIC

Ann Thorac Surg 2009;87:1056 – 65

GENERAL THORACIC

1062

LIN ET AL THORACIC ESOPHAGEAL SQUAMOUS CELL CANCER

Ann Thorac Surg 2009;87:1056 – 65

Table 5. Numbers of Positive Lymph Nodes Metastasis and American Joint Committee on Cancer TNM Status Groups of Positive LN Metastasis, No. (%) Variable T status T1 T2 T3 T4 N status N– N1 M1a M1b M status M0 M1a M1b Cancer stage (AJCC) I II III IV

Positive LN Metastasis

p Value

Patients

Mean No. ⫾ SD

Kruskal-Wallis

9 22 42 36

0.2 ⫾ 0.7 1.0 ⫾ 1.4 2.6 ⫾ 5.2 3.2 ⫾ 3.8

42 25 19 23

0.0 ⫾ 0.0 3.5 ⫾ 6.3 3.2 ⫾ 1.6 4.5 ⫾ 4.2

67 19 23

1.3 ⫾ 4.2 3.2 ⫾ 1.6 4.5 ⫾ 4.2

8 33 26 42

0.0 ⫾ 0.0 0.4 ⫾ 0.8 2.9 ⫾ 6.4 3.9 ⫾ 3.3

0 (n ⫽ 42)

1–3 (n ⫽ 44)

ⱖ4 (n ⫽ 23)

8 (88.9) 11 (50.0) 15 (35.7) 8 (22.2)

1 (11.1) 10 (45.5) 16 (38.1) 17 (47.2)

0 (0.0) 1 (4.5) 11 (26.2) 11 (30.6)

42 (100.0) 0 (0.0) 0 (0.0) 0 (0.0)

0 (0.0) 20 (80.0) 10 (52.6) 14 (60.9)

0 (0.0) 5 (20.0) 9 (47.4) 9 (39.1)

42 (62.7) 0 (0.0) 0 (0.0)

20 (29.9) 10 (52.6) 14 (60.9)

5 (7.5) 9 (47.4) 9 (39.1)

8 (100.0) 26 (78.8) 8 (30.8) 0 (0.0)

0 (0.0) 7 (21.2) 13 (50.0) 24 (57.1)

0 (0.0) 0 (0.0) 5 (19.2) 18 (42.9)

⬍0.001

0.001

⬍0.001

⬍0.001

⬍0.001

⬍0.001

⬍0.001

AJCC ⫽ American Joint Committee on Cancer;

p Value Linear-by-Linear

⬍0.001

LN ⫽ lymph node.

lymph node metastasis after every 7.8 lymph nodes dissected). The incidence of positive nodal metastasis as a function of different T status increased gradually from T1 (2.0%, 1 of 50), T2 (5.0%, 1 of 20), and T3 (12.6%, 1 of 7.9) to T4 (20.6%, 1 of 4.8; p ⫽ 0.001, Kruskal-Wallis; Table 6, upper panel). In other words, one positive lymph node

can be found in every 50 lymph nodes dissected in T1 patients, every 20 lymph nodes dissected in T2 patients, every 7.9 lymph nodes dissected in T3 patients, and every 4.8 lymph nodes dissected in T4 patients. When the arbitrary number of 20 was used as the cutoff value for minimal lymph nodes required to be dissected,

Table 6. The Relationship Between T Status and Number of Positive Lymph Node Metastasis by Extent of Lymph Node Dissection T Status

No.

Total Dissected LN (Mean ⫾ SD)

Detection Rate (%) (Mean ⫾ SD)

T1 T2 T3 T4 Overall

9 22 42 36 109

18.1 ⫾ 12.6 18.5 ⫾ 8.4 23.7 ⫾ 15.6 20.2 ⫾ 11.8 21.0 ⫾ 12.9

2.0 ⫾ 6.0 5.0 ⫾ 6.0 12.6 ⫾ 17.3 20.6 ⫾ 22.6 12.8 ⫾ 18.2

p Value Kruskal-Wallis 0.001

Total Dissected LN ⱕ20 LN Dissected (n ⫽ 65)

⬎20 LN Dissected (n ⫽ 44)

LN Metastasis, Mean No. T1 T2 T3 T4 Overall

9 22 42 36 109

LN ⫽ lymph node;

0.3 0.7 1.5 2.5 1.5 SD ⫽ standard deviation.

0.0 1.9 4.0 4.2 3.5

0.626 0.054 0.125 0.180 0.008

more positive lymph node metastasis was found in the patients undergoing lymph node dissection exceeding 20 than less than 20 (3.5 positive lymph node metastasis vs 1.5 positive lymph node metastasis, p ⫽ 0.008, t test; Table 6, lower panel). For the patients undergoing dissection of more than 20 lymph nodes, the mean positive node metastasis in T2, T3, and T4 lesions was 1.9, 4.0, and 4.2, respectively, and they were greater than the patients undergoing lymph node dissection of less than 20, especially in T2 lesions (p ⫽ 0.054; Table 6, lower panel).

Comment 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, linearby-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

LIN ET AL THORACIC ESOPHAGEAL SQUAMOUS CELL CANCER

1063

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 ⱖ4 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.

GENERAL THORACIC

Ann Thorac Surg 2009;87:1056 – 65

GENERAL THORACIC

1064

LIN ET AL THORACIC ESOPHAGEAL SQUAMOUS CELL CANCER

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, ⱖ4) 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

Ann Thorac Surg 2009;87:1056 – 65

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 NT lymph node metastasis (regional nodes), 7 had positive NA lymph node metastasis (nonregional nodes), and 6 had both positive NT and NA 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 ⱖ4) 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.

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

References 1. Li JY, Liu BQ, Li GY, Chen ZJ, Sun XI, Rong SD. Atlas of cancer mortality in the People’s Republic of China. An aid for cancer control and research. Int J Epidemiol 1981;10:127–33. 2. Li JY. Cancer mapping as an epidemiologic research resource in China. Recent Results Cancer Res 1989;114:115–36. 3. Law S, Wong J. Esophageal cancer surgery: lessons from 1,200 resections. Hawaii Med J 2004;63:203–5. 4. Wu IC, Lu CY, Kuo FC, et al. Interaction between cigarette, alcohol and betel nut use on esophageal cancer risk in Taiwan. Eur J Clin Invest 2006;36:236 – 41. 5. Wong J. Esophageal resection for cancer: the rationale of current practice. Am J Surg 1987;153:18 –24. 6. Hsu CP, Chen CY, Hsia JY, Shai SE. Prediction of prognosis by the extent of lymph node involvement in squamous cell carcinoma of the thoracic esophagus. Eur J Cardiothorac Surg 2001;19:10 –3. 7. Tsai CH, Hsu HS, Wang LS, et al. Surgical results of squamous cell carcinoma of the esophagus in young patients. J Chin Med Assoc 2003;66:288 –93. 8. Wang HW, Chu PY, Kuo KT, et al. A reappraisal of surgical management for squamous cell carcinoma in the pharyngoesophageal junction. J Surg Oncol 2006;93:468 –76. 9. Wang LS, Chow KC, Chi KH, et al. Prognosis of esophageal squamous cell carcinoma: analysis of clinicopathological and biological factors. Am J Gastroenterol 1999;94:1933– 40. 10. American Joint Committee on Cancer. AJCC cancer staging mannual. 6th ed. Philadelphia: Lippincott-Raven; 2002.

11. Ellis FH Jr, Heatley GJ, Krasna MJ, Williamson WA, Balogh K. Esophagogastrectomy for carcinoma of the esophagus and cardia: a comparison of findings and results after standard resection in three consecutive eight-year intervals with improved staging criteria. J Thorac Cardiovasc Surg 1997; 113:836 – 46; discussion 846 – 8. 12. Rice TW, Blackstone EH, Rybicki LA, et al. Refining esophageal cancer staging. J Thorac Cardiovasc Surg 2003;125: 1103–13. 13. Wijnhoven BP, Tran KT, Esterman A, Watson DI, Tilanus HW. An evaluation of prognostic factors and tumor staging of resected carcinoma of the esophagus. Ann Surg 2007;245:717–25. 14. Hofstetter W, Correa AM, Bekele N, et al. Proposed modification of nodal status in AJCC esophageal cancer staging system. Ann Thorac Surg 2007;84:365–73; discussion 374. 15. Brown LM. The role of race/ethnicity in the epidemiology of esophageal cancer. J Assoc Acad Minor Phys 2000;11:32–7. 16. Crehange G, Bosset M, Lorchel F, et al. Tumor volume as outcome determinant in patients treated with chemoradiation for locally advanced esophageal cancer. Am J Clin Oncol 2006;29:583– 87. 17. Chyou PH, Nomura AM, Stemmermann GN. Diet, alcohol, smoking and cancer of the upper aerodigestive tract: a prospective study among Hawaii Japanese men. Int J Cancer 1995;60:616 –21.

LIN ET AL THORACIC ESOPHAGEAL SQUAMOUS CELL CANCER

1065

18. Zambon P, Talamini R, La Vecchia C, et al. Smoking, type of alcoholic beverage and squamous-cell oesophageal cancer in northern Italy. Int J Cancer 2000;86:144 –9. 19. Rizk N, Venkatraman E, Park B, Flores R, Bains MS, Rusch V. The prognostic importance of the number of involved lymph nodes in esophageal cancer: implications for revisions of the American Joint Committee on Cancer staging system. J Thorac Cardiovasc Surg 2006;132:1374 – 81. 20. de Manzoni G, Pedrazzani C, Verlato G, et al. Comparison of old and new TNM systems for nodal staging in adenocarcinoma of the gastro-oesophageal junction. Br J Surg 2004;91: 296 –303. 21. Eloubeidi MA, Desmond R, Arguedas MR, Reed CE, Wilcox CM. Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: the importance of tumor length and lymph node status. Cancer 2002;95:1434 – 43. 22. Altorki N, Kent M, Ferrara C, Port J. Three-field lymph node dissection for squamous cell and adenocarcinoma of the esophagus. Ann Surg 2002;236:177– 83. 23. Siewert JR, Stein HJ, Feith M, Bruecher BL, Bartels H, Fink U. Histologic tumor type is an independent prognostic parameter in esophageal cancer: lessons from more than 1,000 consecutive resections at a single center in the Western world. Ann Surg 2001;234:360 – 67; discussion 368 –9.

INVITED COMMENTARY Surgical resection remains the cornerstone of treatment of esophageal cancer. However, there is less certainty regarding the extent of lymph node dissection necessary at the time of surgery. Some hold that the disease is systemic at the time of diagnosis and that an extensive nodal dissection only adds to the morbidity of the operation without a meaningful improvement in survival. Others, including our group, have argued that extended nodal dissection improves staging, local disease control, and perhaps even survival. The authors of the current article provide further evidence that lymph node resection does matter. Lin and colleagues [1] should be complimented for their attention to detail in the conduct of their operations and in the cataloguing of their data. They present a systematic review of 109 patients undergoing primary resection for squamous cell cancer of the esophagus. The authors meticulously documented the primary site of the tumors as well as the sites of lymph node metastases. Several points from the article merit recognition. Their data show that esophageal cancer readily and frequently spreads to nonregional lymph nodes. Sixtytwo percent of their patients with nodal metastases had pathologically confirmed involvement of the nonregional lymph nodes, which was stage IV by the current staging system. This emphasizes the importance of multi-level lymph node dissection. Furthermore, the 26-month median survival in this group of patients after surgery alone calls into question whether they should truly be considered as stage IV. The second important point in the article is that the number of involved lymph nodes rather than the location is the important determinant of survival. Other groups have noted this as well, with minor differences in the

© 2009 by The Society of Thoracic Surgeons Published by Elsevier Inc

cut-off values. It seems that the next iteration of the esophageal staging system should include a nodal designation based on the number of involved lymph nodes. Finally, the concept put forth by the authors regarding the requirement for a minimal number of lymph nodes dissected should be emphasized. Unfortunately, this is not the pattern of practice in the United States. A recent analysis of the Surveillance, Epidemiology and End Results (SEER) data for esophageal cancer showed that the median number of total lymph nodes resected in over 5,600 esophagectomies was only eight [2]. Clearly, we have to do a better job in this regard, if for no other reason than to adequately stage these patients and subsequently better evaluate our treatment modalities. Secondary benefits such as reduced locoregional recurrence and enhanced survival may follow. Nasser Altorki, MD Brendon M. Stiles, MD Department of Cardiothoracic Surgery Weill Medical College of Cornell University 525 East 68th St New York, NY 10021 e-mail: [email protected]; [email protected]

References 1. Lin C-S, Chang S-C, Wei Y-H, et al. Prognostic variables in thoracic esophageal squamous cell carcinoma. Ann Thorac Surg 2009;87:1056 – 65. 2. Schwarz RE, Smith DD. Clinical impact of lymphadenectomy extent in resectable esophageal cancer. J Gastrointest Surg 2007;11:1384 –93.

0003-4975/09/$36.00 doi:10.1016/j.athoracsur.2008.12.068

GENERAL THORACIC

Ann Thorac Surg 2009;87:1056 – 65