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10.1245/s10434-006-9094-9
Annals of Surgical Oncology 14:299-305 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Nodal Staging in Adenocarcinoma of the Gastro-Esophageal Junction. Proposal of a Specific Staging System

Corrado Pedrazzani1, Prof. Giovanni deManzoni2, Daniele Marrelli1, Simone Giacopuzzi2, Giovanni Corso1, Marco Bernini2 and Prof. Franco Roviello1

1 Department of Human Pathology and Oncology, Unit of Surgical Oncology, University of Siena, Policlinico Le Scotte, V. le Bracci 2, 53100, Siena, Italy
2 First Department of General Surgery, University of Verona, Ospedale Civile Maggiore, P. le Stefani 1, 37126, Verona, Italy

Correspondence: Address correspondence and reprint requests to: Prof. Giovanni de Manzoni, E-mail: gdemanzon{at}mail.univr.it; Prof. Franco Roviello, E-mail: roviello{at}unisi.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: This study was aimed at developing a proper nodal staging system for GEJ adenocarcinoma.

Methods: The study analyzed 113 patients with GEJ adenocarcinoma consecutively resected at the Department of General Surgery and Surgical Oncology of the University of Siena and at the Department of General Surgery of the University of Verona. Both the number (TNM) and site (JGCA) of lymph node metastasis was evaluated in considering nodal staging.

Results: The TNM and JGCA staging systems coincided only in 56.3% of cases. Nodal involvement resulted to be the most important prognostic factor considering both the staging systems (P < 0.001). An extremely poor prognosis and a prominent risk of death were observed for patients with more than six metastatic nodes (TNM pN2-3) as well as for patients with involvement of second and third tier nodes (JGCA pN2-3) (P < 0.001). The combined prognostic significance of the two classifications showed a similar risk of death for patients with less than seven metastatic nodes (TNM pN1) located beyond the first tier (JGCA pN2-3) and for patients with more than six involved nodes (TNM pN2-3) independently from the interested level (JGCA pN1-3). Accordingly, these classes were pooled together and four classes considered: pN0, TNM-JGCA pN1, TNM pN2-3 or JGCA pN2-3, M1a (P < 0.001).

Conclusions: The combination of the TNM and JGCA staging systems herein proposed is extremely practical from a clinical point of view and leads to the stratification of pN+ patients in two classes only with very different risk of death.

Key Words: Gastro-esophageal junction adenocarcinoma • Lymph node metastasis • TNM classification • JGCA classification


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Gastro-esophageal junction (GEJ) adenocarcinoma is considered as a distinct clinical entity by the majority of authors,1–3 nonetheless it has been not so far considered as a specific neoplasm in the International Union Against Cancer (UICC) and American Joint Committee on Cancer (AJCC) rules.4 According to the current TNM staging system, adenocarcinomas located in the cardia region are classified as esophageal if more than 50% of the tumor involves the esophagus, if less than 50% as gastric.4

The nodal staging of GEJ adenocarcinoma is complicated by the regional lymphatic drainage of the tumor that is not adequately taken into account by the present pN classification.5,6 A previous experience by our group showed lymph node metastasis to be the most important prognostic factor, whether considering the site (TNM, 4th edition) or number (TNM, 5th edition) of involved nodes. Among patients with a similar number of involved lymph nodes, the site of metastasis was found to be a strong predictor of survival. On this basis, it is our conviction that GEJ adenocarcinoma requires a specific lymph nodal classification which should consider both the number and location of metastatic nodes.7

The aim of the present study was to develop a proper nodal staging for GEJ adenocarcinoma.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population
The study includes 113 patients with GEJ adenocarcinoma consecutively operated on at the Department of General Surgery and Surgical Oncology of the University of Siena, between January 1995 and December 2003 and at the Department of General Surgery of the University of Verona, between January 1988 and December 2003. Median age of the cohort was 68 years (range 27–90) with a male to female ratio of 4.65 to 1. Clinical, histopathological and follow-up data of all the patients were prospectively collected.

Definition and Inclusion Criteria
GEJ adenocarcinoma was defined according to the well-known Siewert classification.1 The most important inclusion criteria were: histologically proven adenocarcinoma, Siewert type II and III tumors, absence of systemic metastases, no preoperative chemo and/or radiotherapy, potentially curative (R0) surgery, no postoperative mortality, no history of secondary malignancy, possibility of follow-up with a minimum period of 24 months. Siewert type I was not considered since it is not usually classified according to the present TNM and JGCA staging systems.

Surgery
The choice of surgical approach was based on the tumor location, and on the length of invasion of the esophagus and stomach with the principal aim to achieve complete surgical resection. Surgical resection and mode of reconstruction have been previously described in detail.8 Briefly, the standard procedure for type III tumors was a total gastrectomy with transhiatal resection of the distal esophagus. Type II tumors were treated by subtotal esophagectomy with proximal gastric resection through a right thoracotomy (Ivor–Lewis procedure) or by total gastrectomy with transhiatal or transthoracic resection of the distal esophagus. The mode of reconstruction was a gastric tube after subtotal esophagectomy, while a jejunal Rouxen-Y reconstruction was performed after total gastrectomy.

Lymph node dissection was classified according to the Japanese Gastric Cancer Association (JGCA, 2nd edition) rules: D1 lymphadenectomy (resection of perigastric nodes in position 1–4sb), D2 lymphadenectomy (resection of nodes in position 1–11) and D3 lymphadenectomy (resection extended to the nodes in position 12–16).9 The preferred lymph node dissection consisted of removal of the lower posterior mediastinum nodes and a D2–D3 abdominal lymphadenectomy. D1 dissection was reserved for patients at high-risk for complications.

Staging
Pathologic lymph node (pN) staging was evaluated according to the number and site of nodal metastasis. The number-based classification (TNM, 5th edition) followed the criteria provided by the UICC and AJCC rules,4 while the site-based classification adhered to the criteria stated by the JGCA.9 When considering TNM staging system, positive nodes in the retropancreatic (No. 13) and para-aortic (No. 16) stations were considered as distant metastasis (M1a), otherwise middle para-aortic nodes (No. 16a2 and 16b1) were considered as pN3 when considering the JGCA classification. According to the TNM suggestion, cases in which examined lymph nodes were negative and less than 15 lymph nodes were retrieved were classified as pN0.10

The histological classification followed the criteria of Lauren, mixed type tumors were considered together with diffuse type (non-intestinal type).

After discharge from hospital all patients were followed-up after 4 months and at 6 month intervals until their death or the time of study (December 2005). None of the patients was lost to follow-up. The mean (±SD) follow-up period for the surviving patients was 67.5 (±46.4) months (median 54.8; range 24.1–190.6).

Statistical Analysis
Survival curves were estimated using the Kaplan–Meier method and compared by the log-rank test. Multivariate analysis was performed by Cox regression model by taking into account the following risk factors: age (> median vs. ≥ median), sex (female vs. male), tumor location according to Siewert (type IIII vs. type II), Lauren type (non-intestinal vs. intestinal), depth of invasion (pT2, pT3 and pT4 vs. pT1) and nodal involvement, expressed either as the site (JGCA pN1, pN2 and pN3/M vs. pN0) or the number (TNM pN1, pN2-3 and M1a vs. pN0) of metastatic nodes. As there were just seven cases with more than 15 involved nodes (TNM pN3) they were considered together with TNM pN2 in the survival analysis. Likewise the two cases with involvement of third tier nodes (JGCA pN3) and not classified as M1a by the TNM staging system were considered together with JGCA pN2. Deaths from causes other than GEJ adenocarcinoma were considered censored observations at the time of death. As the site and the number of metastatic nodes were highly collinear, their impact on survival was evaluated separately by performing two different analyses. Furthermore, the two variables were joined to build up a new variable with the following levels: pN0; JGCA pN1 with one to six positive nodes (TNM pN1); JGCA pN2-3 with one to six positive nodes (TNM pN1); JGCA pN1-3 with more than six positive nodes (TNM pN2-3); M1a according to the TNM staging system.

Analyses were performed using the Statistical Product and Service Solutions, SPSS 12.0 for Windows, XP, SPSS Inc., Chicago, IL.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of the 113 patients, a total of 4,303 lymph nodes were dissected, with a mean (±SD) of 38.1 (±20.8) retrieved nodes per case (median 33; range 2–108). The mean (±SD) number of metastatic nodes was 6.1 (±7.6) (median 4; range 0–38) in the overall series and 8.6 (±7.7) (median 6; range 1–38) in pN+ patients.

The majority of patients underwent an extended (D2 lymphadenectomy in 51 cases) or super-extended lymph node dissection (D3 lymphadenectomy in 47 cases). The number of retrieved nodes according to the type of lymphadenectomy is reported in Fig. 1Go. As expected, the number of excised nodes significantly increased with the extension of lymph node dissection (P < 0.001).


Figure 1
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  		FIG. 1. Mean (±SD) number of retrieved nodes according to the extent of lymph node dissection. D1, D2 and D3 lymphadenectomy was performed in 15, 51 and 47 cases, respectively (P < 0.001).

 
The mean (±SD) number of dissected nodes were 35.5 (±19.9) (median 32.5; range 2–108) for type II and 40.8 (±21.5) (median 33; range 14–108) for type III (P = 0.179).

Correlation Between the Site and Number of Lymph Node Metastases
The pN allocation according to the two staging systems is shown in Table 1Go. TNM and JGCA classifications were not superimposed. Among the 39 patients classified as TNM pN1, 12 (30.8%) were upstaged as pN2 by the JGCA staging system. Furthermore, 8 out of the 23 patients (34.8%) classified as TNM pN2 changed their stage, seven patients (30.4%) were down-staged as JGCA pN1, whereas one patient (4.3%) was up-staged as pN3. Eight patients showed more than 15 metastatic nodes (TNM pN3), among which seven (87.5%) were classified as pN2 by the JGCA staging system. Eight patients showed metastases to para-aortic nodes (No. 16a2 and 16b1), they were considered M1a by the TNM and pN3 by the JGCA staging system. Otherwise, two patients with involvement of retropancreatic nodes (No. 13) were considered metastatic by the JGCA as well as the TNM classification.


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  		TABLE 1. Joint distribution of the TNM and JGCA pN classifications
 
The mean (±SD) number of metastatic nodes were 4.4 (±3.2) (median 3.5; range 1–13) for JGCA pN1 tumors, 10.6 (±7.4) (median 9; range 1–32) for pN2 and 15.0 (±11.6) (median 9; range 5–38) for pN3 (P < 0.001).

Survival Analysis
The overall median (95% CI) survival time for the 113 patients was 26.2 (18.3–34.1) months with 3- and 5-year survival rates of 43.9 and 34.9%.

Kaplan–Meier curves and Cox regression model for the TNM and JGCA classifications are reported in Fig. 2AGo and Table 2Go. An extremely poor prognosis and a prominent risk of death were observed for patients with more than six metastatic nodes (TNM pN2-3) as well as for patients with involvement of second and third tier nodes (JGCA pN2-3) (P < 0.001). At multivariate analysis, nodal involvement resulted to be the most important prognostic factor considering both the staging systems (Table 2Go).


Figure 2
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  		FIG. 2. A Kaplan–Meier estimates of survival probability according to the TNM classification for the 113 patients who underwent curative surgery for GEJ adenocarcinoma. Median (95% CI) survival time was: Not reached for pN0; 36.6 (21.1–52.1) months for pN1; 14.7 (11.1–18.2) months for pN2-3; 10.1 (3.3–16.8) months for M1a (P < 0.001). B Kaplan–Meier estimates of survival probability according to the JGCA classification for the 113 patients who underwent curative surgery for GEJ adenocarcinoma. Median (95% CI) survival time was: Not reached for pN0; 39.4 (21.9–57.0) months for pN1; 17.7 (15.9–19.5) months for pN2; 10.8 (6.8–14.7) months for pN3-M (P < 0.001).

 

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  		TABLE 2. Relative risks of death from GEJ adenocarcinoma as a function of pN status
 
Cox regression model analysing the combined prognostic significance of the two classifications is presented in Table 3Go. The risk of death for patients with less than seven metastatic nodes (TNM pN1) located beyond the first tier (JGCA pN2-3) was significantly higher with respect to patients with less than seven metastatic nodes (TNM pN1) within the first tier (JGCA pN1); on the other hand, the risk of death was comparable with respect to patients with more than six involved nodes (TNM pN2-3) independently from the interested level (JGCA pN1-3) (Table 3Go).


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  		TABLE 3. Relative risks of death from GEJ adenocarcinoma according to the joint distribution of site (JGCA) and number (TNM) of positive nodes
 
Accordingly, patients with less than seven meta-static nodes (TNM pN1) located beyond the first tier (JGCA pN2-3) and patients with more than six involved nodes (TNM pN2-3) were pooled together and four pN classes were hence considered: pN0, TNM-JGCA pN1, TNM pN2-3 or JGCA pN2-3, M1a (Fig. 3Go).


Figure 3
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  		FIG. 3. Kaplan–Meier estimates of survival probability according to the joint distribution of the TNM and the JGCA classifications for the 113 patients who underwent curative surgery for GEJ adenocarcinoma. Median (95% CI) survival time was: not reached for pN0; 61.2 (29.8–92.5) months for <7 nodes and JGCA pN1; 17.4 (13.5–21.2) months for >6 nodes or JGCA pN2-3; 10.1 (3.3–16.8) months for M1a (P < 0.001).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The major findings of the present study are: (1) the site-based (JGCA) and the number-based (TNM) pN staging systems were not superimposed; (2) nodal involvement confirmed to be the main prognostic factor, either considering the JGCA or the TNM classifications; (3) little chance of survival was observed for patients with more than six metastatic nodes (TNM pN2-3) or involvement of second tier nodes or beyond (JGCA pN2-3); (4) the influence on survival showed by the JGCA as well as by the TNM staging systems was adequately represented after combining the two classifications.

In GEJ adenocarcinoma, as already described for gastric cancer,11,12 the number-based and the site-based nodal staging systems coincided in about 55% of the cases. Noteworthy, only 27 out of the 80 pN+ patients (33.8%) showed involvement of less than seven first tier nodes (Table 1Go).

To minimize confounding factors and better evaluate the prognostic significance and the strength of different features, strict inclusion criteria were adopted. The analysis was hence limited to R0-resected patients who did not undergo preoperative chemo and/or radiotherapy, survived the postoperative phase and reached a minimum follow-up period of 2 years.

In accordance with our previous experiences7,8 and literature results,13–15 lymph nodal involvement confirmed to be the most important factor predicting survival, whether considering the number or the site of metastatic nodes.7 It is our belief that the development of a specific system for nodal staging, which should consider both the level and number of lymph node metastases, is advisable for GEJ adenocarcinoma.

The UICC and AJCC rules do not provide a proper classification for this neoplasia and suggest to consider tumors located in the cardia region as esophageal or gastric dependently from the extent of the oral and aboral involvement.4 Nonetheless, type II and III GEJ adenocarcinoma are staged and treated similarly to gastric cancer by the majority of authors.13–17

Several studies published to date8,14,15 reported no chance of survival when more than 4–6 metastatic nodes were diagnosed. Also in the present experience, the prognosis for patients with more than six meta-static nodes (TNM pN2-3) (Fig. 2AGo) as well as for patients with involvement of second and third tier nodes (JGCA pN2-3) (Fig. 2BGo) was extremely poor. Besides, the risk of death was significantly lower for pN0 cases and patients with less than seven meta-static nodes (TNM pN1) located within the first tier (JGCA pN1) with respect to all other classes (TNM pN2-3 or JGCA pN2-3) (Table 3Go). Consequently, the above mentioned classes were joined together to build up a new pN classification which considers four categories: pN0, patients with less than seven metastatic nodes located within the first tier (TNM-JGCA pN1), patients with more than six involved nodes (TNM pN2-3) or involvement of second tier or beyond (JGCA pN2-3) and M1a (Fig. 3Go).

The TNM classification currently adopted for gastric cancer is widely accepted because of its strength in prognostic stratification, simplicity, reproducibility and low methodological related problems.12,18,19 On the other hand, it is strongly influenced by the surgeon’s attitude toward the extent of lymph node dissection and, even after extended (D2) lymphadenectomy, stage migration occurs in 5–15% of the cases.19,20 Otherwise, the Japanese classification is more functional from the viewpoint of surgical application although definitely more complex to apply.21

The classification herein proposed for GEJ adenocarcinoma, derived from the TNM and JGCA staging systems for gastric cancer, shares the advantages of both and matches properly the aggressiveness of this tumor. In fact, it is straightforward, easy to adopt and extremely practical from a surgical and clinical point of view. Noteworthy, pN+ patients are stratified in two classes only with an extremely different risk of death. In particular, more than 30% of patients classified as pN1 by the actual TNM staging system show a very high risk of death (JGCA pN2-3), in the newly proposed classification these patients change their stage and are more properly regarded as patients with poor prognosis. The possibility to identify a group of patients at very high risk for cancer related death should facilitate the decision making in this highly aggressive tumor.

In conclusion, the newly proposed classification seems to be reliable and to better stratify the risk of death in type II and III GEJ adenocarcinoma. Further studies with a larger number of patients are necessary to confirm the real value of the proposed staging system.


   ACKNOWLEDGMENTS
 
The authors thank Giuseppe Verlato (Unit of Epidemiology and Medical Statistics, University of Verona) for statistical revision of the manuscript. This research was supported by a grant of CNR-MIUR.

Received for publication May 15, 2006. Accepted for publication May 23, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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