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Japanese Journal of Clinical Oncology Pages 248-251

How the Lymph Node Metastases Toward Cervico-Upper Mediastinal Region Affect the Outcome of Patients with Carcinoma of the Thoracic Esophagus
Introduction
Patients and Methods
Statistical Analysis
Results
   Clinicopathological Characteristics of 159 Esophageal Cancer Patients with Nodal Metastasis
   Recurrence and Survival Rates in 93 Esophageal Cancer Patients with Upward Metastasis
Discussion
Acknowledgments
References
How the Lymph Node Metastases Toward Cervico-Upper Mediastinal Region Affect the Outcome of Patients with Carcinoma of the Thoracic Esophagus

How the Lymph Node Metastases Toward Cervico-Upper Mediastinal Region Affect the Outcome of Patients with Carcinoma of the Thoracic Esophagus

Shizuo Nakano, Masamichi Baba, Mario Shimada, Kazusada Shirao, Yasuhiko Noguchi, Chikara Kusano, Shoji Natsugoe, Heiji Yoshinaka, Toshitaka Fukumoto and Takashi Aikou

The First Department of Surgery, Faculty of Medicine, Kagoshima University, Kagoshima, Japan

Background: The aim of this study was to establish whether the site of lymph node metastasis influences the survival of patients with carcinoma of the thoracic esophagus.
Methods: A series of 159 patients with lymph node metastasis who underwent right transthoracic R0 esophagectomy was analyzed retrospectively. Sites of the nodal metastasis were divided into two regions; the neck and/or upper mediastinum above (upward metastasis) and the abdomen and/or lower mediastinum below (downward metastasis) the tracheal carina.
Results: Univariate analysis of prognostic factors revealed the tumor location, distant lymphatic metastasis, number of metastatic nodes and upward metastasis influenced survival, but downward metastasis did not. Multivariate analysis showed that the number of metastatic nodes and upward metastasis were also significant prognostic factors. Thirty-one (33.3%) of the 93 patients with, but only 6 (9.1%) without, upward metastasis had recurrences in the neck and/or upper mediastinum (P = 0.0002). Eighteen (60.0%) of the 30 patients with extranodal invasion in the neck and/or upper mediastinum had recurrence in these regions.
Conclusions: Nodal metastasis in the neck and/or upper mediastinum was a significant risk factor for prognosis, the same as the number of metastatic nodes.

Key words: lymph node metastasis of esophageal carcinoma - extranodal invasion - recurrence after esophagectomy - prognostic factor

INTRODUCTION

During the past decade, subtotal esophagectomy with cervicothoracoabdominal three-field dissection has become an option for the surgical treatment of esophageal cancer, allowing more accurate staging and revealing the pattern of lymph node metastasis (1-3). The recurrent nerve lymphatic chains and the abdominal paracardiac nodes are the lymph nodes most commonly affected by metastatic carcinoma of the thoracic esophagus (4). However, according to the TNM classification (5), the recurrent nerve lymphatic chains in the neck are classified as distant lymph nodes, and those in the upper mediastinum as regional lymph nodes. During the surgery, it is difficult to differentiate the cervical nodes from the upper mediastinal nodes, especially recurrent nerve lymphatic chains. Nowadays, the number of metastatic nodes is considered to be one of the most important prognostic factors (6-8), but whether the site of lymph node metastasis influences patient outcome is unclear. The aim of this study was to determine whether the site of the metastatic nodes influences the survival of patients with carcinomas of the thoracic esophagus.

PATIENTS AND METHODS

From 1983 to 1996, 275 patients with carcinomas of the thoracic esophagus underwent R0 (5) radical esophagectomy through a right thoracotomy and laparotomy. Lymph node metastasis was confirmed histologically in 168 (61.2%) of these 275 patients. Nine (5.3%) of these 168 patients died during primary hospitalization and were excluded from this study, but the remaining 159 with lymph node metastasis were analyzed. This group included 105 and 54 patients who underwent cervicothoracoabdominal three-field dissection and thoracoabdominal two-field dissection with a sampling of the cervical paraesophageal nodes at the time of anastomosis in the neck, respectively. Sites of the nodal metastasis were divided into two regions; the neck and/or upper mediastinum above and the abdomen and/or lower mediastinum below the tracheal carina (upward and downward metastasis, respectively). Patients with upward metastasis mainly had metastasis to the cervical nodes, recurrent nerve lymphatic chains and infra-aortic nodes and those with downward metastasis had metastasis to the subcarinal and paraesophageal nodes and nodes along the left gastric artery. Extranodal invasion was defined as the presence of cancer cells in the connective tissues around the removed nodes detected by histological examination (9,10) (Fig. 1). Tumor recurrence, in particular the first site of recurrence, was examined by carrying out endoscopy, roentgenography, echography and/or computed tomography every 3-6 months after surgery. No patient was lost from follow up during the follow up period from 18 months to 166 months after surgery.


Figure 1. Microscopic view of nodal metastasis and extranodal invasion.(Open arrow): The nest of cancer cells in the lymph node indicates nodal metastasis. (Closed arrow): The nest of cancer cells in the fibro-fatty tissue indicates extranodal invasion. Positive extranodal invasion includes lymphatic vessel invasion (closed arrow) in the fibro-fatty tissue, spillage of cancer cells from the nodal metastasis, or both.

STATISTICAL ANALYSIS

Cancer-specific survival rates were calculated by the Kaplan-Meier method and compared univariately using the Log-rank test. Univariate analysis was performed using The Mann-Whitney U-test or chi-squared test with Yates's correction. The level of significance was set at P < 0.01. Cox's proportional hazards model was used to evaluate the prognostic significance of each clinicopathological factor after adjustment for other covariate effects. Multiple stepwise analysis was carried out using the statistical analysis program SPSS (SPSS Inc., Chicago, IL).

RESULTS

Clinicopathological Characteristics of 159 Esophageal Cancer Patients with Nodal Metastasis

Thirteen parameters were subjected to univariate analysis (Table 1) and the variables that affected patient outcome significantly (P < 0.01) were the tumor location, distant lymphatic metastasis, number of metastatic nodes and upward metastasis. Downward metastasis did not have a significant effect. The incidence of upward metastasis depended upon the tumor location: 13 (100%) of the 13 upper-third, 65 (69.4%) of the middle-third, and 15 (29.4%) of the lower-third of the esophagus. The average numbers of metastatic nodes in the 93 patients with upward metastasis was 8.2 ± 9.8 and that in the 123 patients with downward metastasis was 6.9 ± 8.8 (P = 0.3072). Stepwise logistic regression analysis revealed two independent prognostic factors among the 13 variables, the number of metastatic nodes and upward metastasis (Table 2). Lymph node metastasis involving four or more nodes and the presence of upward metastasis in the neck and/or upper mediastinum had a significant adverse effect on survival. Recurrences occurred in 91 (57.2%) of the 159 patients (Table 3) at one month to 61 months after surgery (average 12 months). Thirty-one (33.3%) of the 93 patients with upward metastasis had recurrences in the neck and/or upper mediastinum, whereas only 6 (9.1%) of the 66 without upward metastasis had recurrences in these regions.

Table 1. Univariate analysis of prognostic factors in 159 esophageal cancer patients with nodal metastasis
Parameter Categories No. of patients Survival rates (%) P-value
2-year 5-year
Age (years old) -62 79 49.7 29.2 0.2907
63- 80 57.0 38.8
Gender Male 149 53.4 33.1 0.7070
Female 10 48.0 36.0
Tumor length (mm) -39 36 72.8 57.9 0.0116
40-79 89 47.7 30.2
80- 34 47.0 20.3
Tumor location Upper 13 64.3 42.9 0.0031
Middle 95 41.3 20.0
Lower 51 70.5 52.5
Type of lymph node dissection 3 field 105 49.6 26.8 0.0206
2 field 54 59.1 48.9
Tumor histology Well 48 50.5 29.0 0.8892
Moderately 79 54.5 36.4
Poorly 26 50.6 32.8
Others 6 62.5 31.2
Depth of invasion p-T1 27 67.9 60.3 0.0695
p-T2 29 52.3 39.8
p-T3 97 51.1 26.8
p-T4 6 25.0 25.0
Distant lymphatic metastasis p-M1 (LYM)a 64 39.2 20.9 0.0017
p-M0 95 62.7 43.2
No. of metastatic nodes 1-3 87 60.8 46.6 0.0002
4 or more 72 43.2 16.7
Vessel invsasion Yes 127 50.7 28.9 0.1079
No 32 62.1 52.6
Extranodal invasion Positive 65 41.3 23.2 0.0117
Negative 94 60.0 39.4
Upward metastasisb Yes 93 41.3 21.2 0.0003
No 66 69.8 52.0
Downward metastasisc Yes 123 55.7 34.1 0.8259
No 36 44.3 29.6
a64 p-M1 (LYM) tumors had distant lymphatic metastasis; 49 in the neck, 12 in the region at the celiac axis and 3 in both regions. bNodal metastasis in the neck and/or upper mediastinum. cNodal metastasis in the abdomen and/or lower mediastinum.

Table 2. Significant prognostic factors in esophageal cancer patients with nodal metastasis analysed by stepwise logistic regression method
Variable Estimated coefficient Standard error Significance Relative risk
Number of metastatic nodes 0.3165 0.1143 0.0056 1.3723
Upward metastasis 0.3326 0.1239 0.0073 1.3946

Table 3. Site of recurrence in 159 patients according to upward metastasis
Site of recurrence Upward metastasis P-value
Yes, n = 93 No, n = 66
The neck and/or upper mediastinum 31 (33.3) 6 (9.1) 0.0002
Other sitesa 31 (33.3) 23 (34.8) 0.9770
Total no. of patients with recurrence 62 (66.7) 29 (43.9) 0.0071
aIndicating downward metastasis and/or blood-borne metastasis. Numbers in parentheses indicate percentages.

Table 4. Site of recurrence in 93 patients with upward metastasis according to extranodal invasion in the neck and/or upper mediastinum
Site of recurrence Extranodal invasion P-value
Positive, n = 30 Negative, n = 63
The neck and/or upper mediastinum 18 (60.0) 13 (20.6) 0.0004
Other sitesa 5 (16.6) 26 (41.3) 0.0342
Total no. of patients with recurrence 23 (76.7) 39 (61.9) 0.2394
aIndicating downward metastasis and/or blood-borne metastasis. Numbers in parentheses indicate percentages.

Recurrence and Survival Rates in 93 Esophageal Cancer Patients with Upward Metastasis

The sites of recurrence in the 93 patients with upward metastasis were analyzed according to the presence of extranodal invasion in the neck and/or upper mediastinum (Table 4). Eighteen (60.0%) of the 30 patients with extranodal invasion in the neck and/or upper mediastinum had recurrences in these regions, whereas only 13 (20.6%) of the 63 without extranodal invasion had recurrence in these regions, regardless of upward metastasis.

DISCUSSION

It is well known that nodal metastasis occurs frequently in patients with esophageal carcinomas and the extent of nodal metastasis, particularly the number of metastatic nodes, has been found to be a definitive prognostic factor (8). Skinner et al. (11) reported that the critical number of metastatic nodes was three or four and Matsubara et al. (12) analyzed 171 patients who underwent three-field lymphadenectomy and found that the outcome was unfavorable when more than seven nodes were involved. In our study, univariate and multivariate analyses indicated that the number of metastatic nodes was one of the most significant prognostic factors, as was the site of nodal metastasis. Nodal metastasis in the neck and/or upper mediastinum (upward metastasis) was a poor prognostic factor, whereas nodal metastasis in the abdomen and/or lower mediastinum (downward metastasis) was not. In our series, recurrences were observed frequently in the neck and/or upper mediastinum in patients with upward metastasis. Skinner (13) stated that during embryonic life, the esophagus distal to the tracheal bifurcation had a mesoesophagus, which determined the direction of its vascular and lymphatic drainage, whereas the esophagus proximal to the tracheal bifurcation had no such mesoesophagus. Consequently, the lymphatic flow in the neck and/or upper mediastinum is more complicated than that in the proximal regions and this may explain why recurrences are observed so often in the neck and/or upper mediastinum, even after extended dissection. Gatzinsky et al. (14) found that 51% of patients with nodal metastasis had perinodal carcinomatous involvement (extranodal invasion). Similarly, Baba et al. (4) demonstrated that the incidence of extranodal invasion correlated with the number of metastatic nodes and that extranodal invasion occurred most frequently in the upper gastric region and in the region along the recurrent nerves. Watanabe et al. (15) reported that 16 of 18 patients with perinodal invasion died of recurrence within one year of surgery. In fact, in our series, 18 (60.0%) of the 30 patients with extranodal invasion in the neck and/or upper mediastinum had recurrences in these regions. Therefore, nodal metastasis in the neck and/or upper mediastinum accompanying extranodal invasion was deemed equivalent to systemic disease.

Acknowledgments

This study was presented and received an award for excellence at the 26th Conference of the Japanese Society for Cancer and Lymph Node Research. The authors thank Dr Hiromasa Fujita, The First Department of Surgery, Kurume University School of Medicine, for his invaluable assistance with the preparation of this manuscript.

References

1. Kato H, Watanabe H, Tachimori Y, Iizuka T. Evaluation of neck lymph node dissection for thoracic esophageal carcinoma. Ann Thorac Surg 1991;51:931-5. MEDLINE Abstract

2. Isono K, Sato H, Nakayama K. Results of a nationwide study on the three-field lymph node dissection of esophageal cancer. Oncology 1991;48:411-20. MEDLINE Abstract

3. Fujita H, Kakegawa T, Yamana H, Shima I, Toh Y, Tomita Y, et al. Mortality and morbidity rates, postoperative course, quality of life, and prognosis after extended radical lymphadenectomy for esophageal cancer - comparison of three-field lymphadenectomy with two-field lymphadenectomy. Ann Surg 1995;222:654-62. MEDLINE Abstract

4. Baba M, Aikou T, Natsugoe S, Kusano C, Shimada M, Kimura S, et al. Lymph node and perinodal tissue involvement in patients with esophagectomy and three-field lymphadenectomy for carcinoma of the esophagus. J Surg Oncol 1997;64:12-6. MEDLINE Abstract

5. Hermanek P, Sobin LH, editors. International Union Against Cancer (UICC) TNM Classification of Malignant Tumours, 4th edn, 2nd rev. Berlin: Springer-Verlag 1992.

6. Siewert JR, Roder JD. Lymphadenectomy in esophageal cancer surgery. Dis Esophagus 1992;5:91-7.

7. Desai PB, Deshpande RK, Patil PK, Mistry RC. Radical lymphadenectomy in esophageal cancer: does it improve survival? Dis Esophagus 1992;5:99-104.

8. Baba M, Aikou T, Yoshinaka H, Natsugoe S, Fukumoto T, Shimazu H, et al. Long-term results of subtotal esophagectomy with three-field lymphadenectomy for carcinoma of the thoracic esophagus. Ann Surg 1994;219:310-6. MEDLINE Abstract

9. Yoshinaka H, Shimazu H, Natsugoe S, Haraguchi Y, Shimada M, Baba M, et al. Histopathological features of the lymph node metastases in patients with thoracic esophageal cancer. Nippon Geka Gakkai Zasshi 1992;93:1289-96 (in Japanese). MEDLINE Abstract

10. Natsugoe S, Mueller J, Kijima F, Aridome K, Shimada M, Shire K, et al. Extranodal connective tissue invasion and the expression of desmosomal glycoprotein 1 in squamous cell carcinoma of the oesophagus. Br J Cancer 1997;75:892-7. MEDLINE Abstract

11. Skinner DB, Ferguson MK, Soriano A, Little AG, Staszak VM. Selection of operation for esophageal cancer based on staging. Ann Surg 1986;204:391-401. MEDLINE Abstract

12. Matsubara T, Ueda M, Yanagida O, Nakajima T, Nishi M. How extensive should lymph node dissection be for cancer of the thoracic esophagus? J Thorac Cardiov Surg 1994;107:1073-8.

13. Skinner DB. En bloc resection for neoplasms of the esophagus and cardia. J Thorac Cardiov Surg 1983;85:59-71.

14. Gatzinsky P, Berglin E, Dernevik L, Larsson I, William-Olsson G. Resectional operations and long-term results in carcinoma of the esophagus. J Thorac Cardiov Surg 1985;89:71-6.

15. Watanabe H, Kato H, Tachimori Y, Itabashi M. Malignancy of lymph node metastasis, and the lymphatic spread into the mediastinum. In: Kakegawa T, editor. Shoukakibyo Seminar 41. Tokyo: Herusu Shuppan 1990:55-62 (in Japanese).

Received January 11, 1999; accepted March 10, 1999
For reprints and all correspondence: Shizuo Nakano, The First Department of Surgery, Faculty of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-0075, Japan. E-mail: nakano{at}med1.kufm.kagoshima-u.ac.jp

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Last modification: 27 May 1999
Copyright© 1999 Foundation for Promotion of Cancer Research.
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