Japanese Journal of Clinical Oncology

INTRODUCTION

The prognosis of patients with gastric cancer is related to depth of tumor invasion and to the presence of lymph node, liver and peritoneal metastases. All these factors are taken into account as staging factors in the General Rules for Gastric Cancer Study in Surgery and Pathology of Japan (1). Among these factors, lymph node metastasis was found to be an independent prognostic factor only in multivariate analysis (2). Since this study, many investigators have reported that the prognosis of surgically treated patients is affected by the number of metastatic lymph nodes (3-6). Recently, the Union Internacional Contra la Cancrum (UICC) adopted the new TNM classification according to the number of metastatic lymph nodes, which relates closely to the prognosis of gastric cancer (7).

Activated carbon particles (CH40) are taken up selectively by lymphatics after injection into the tissue and draining regional lymph nodes are thereby colored black (8,9). We have employed CH40 to aid extended systematic lymph node dissection and chemotherapy of lymph node metastasis of gastric cancer (10,11). Blackened lymph nodes extend widely from the perigastric to the para-aortic nodes are identified from other structures. Using this technique, even very small nodes can be easily identified for pathological examination. Intra-lymph node injection of CH40 is therefore a potentially very valuable method for the detailed analysis of lymph node involvement in gastric cancer.

In the present study, we investigated the number and anatomical extent of metastatic lymph nodes in patients with surgically resected gastric cancer who received intra-lymph node injection of CH40 and analyzed retrospectively the relationship with long-term outcome.

MATERIALS AND METHODS

Activated carbon particles (CH40, Mitsubishi Kasei, Tokyo, Japan) with a specific surface area of 1480 m²/g and a diameter of 20 nm were prepared as described by Hagiwara et al. (9). After injection into tissues, CH40 is taken up selectively by lymphatics and regional lymph nodes are subsequently colored black (8,9). A 1 ml volume of CH40 solution was injected directly into a regional lymph node close to the tumor using a butterfly needle immediately after laparotomy. It was injected very slowly over a period of about 3 min.

A total of 200 patients, 120 (60%) of whom were men, with primary gastric cancer, who underwent gastrectomy with regional lymph node dissection and received intra-lymph node injection of CH40 at the First Department of Surgery, Kyoto Prefectural University of Medicine, between 1986 and 1994 were analyzed. The mean age of the patients was 58.7 years (range 22-83 years). No patients had evidence of distant metastasis, e.g. to the liver or peritoneum, or had other malignancies.

The number of dissected lymph nodes was determined by examination of the clinicopathologic records. The number of metastatic lymph nodes was divided into four groups, viz. patients without lymph node metastasis and those with 1-3, 4-9 and >9 metastatic lymph nodes.

The regional lymph nodes of the stomach were classified into four compartments using the rules of the Japanese Research Society for Gastric Cancer (JRSGC). Compartment I consists of the perigastric lymph nodes. Compartment II consists of lymph nodes along the left gastric artery, along the common hepatic artery, around the celiac axis and along the splenic artery. Compartment III consists of lymph nodes in the hepatoduodenal ligament, at the posterior aspect of the head of the pancreas and at the root of the mesentery of the transverse colon. When the cancer is located in the lower third of the stomach, lymph nodes along the splenic artery are classified as compartment III. Compartment IV consists of lymph nodes along the superior mesenteric artery and the para-aortic lymph nodes (1). The anatomical extent of lymph node metastases was divided into five categories, viz. n0 (no lymph node metastasis microscopically), n1 (lymph nodes of compartment I involved), n2 (compartment II involved), n3 (compartment III involved) and n4 (compartment IV involved), according to the rules of the JRSGC (1). The anatomical level of lymph node dissection was divided into four groups. Dl included complete dissection of compartment I, D2 compartments I and II, D3 compartments I, II and III and D4 all four compartments, according to the rules of the JRSGC.

The relationship between the number of metastatic lymph nodes and the anatomical extent was analyzed. Cumulative survival rates, including operative mortality, were calculated using the Kaplan-Meier method (12). No patient was lost to follow-up. Statistically significant differences in cumulative survival rate were examined by the log-rank test (13). In the multivariate analysis, independent prognostic factors for survival were determined using a Cox proportional hazard model (14). We chose age, gender, depth of cancer invasion, histology, anatomical level of lymph node dissection, number of metastatic lymph nodes and anatomical extent of metastatic lymph nodes as prognostic variables. The depth of tumor invasion was graded T1, T2, T3 or T4, according to the rules of the JRSGC (1).

RESULTS

Of 200 patients, 27 (15%), 131(72.8%) and 22 (12.2%) underwent curative gastrectomy with D1, D2,3 and D4 lymph node dissection, respectively (Table 1). Statistically significant differences in the numbers of removed lymph nodes were found between D1 and D2,3 (P < 0.05) and between D2,3 and D4 (P < 0.001). In all, 8509 dissected lymph nodes were removed in the 200 patients. The numbers of lymph nodes colored black by CH40 is shown in Table 2. There were no significant differences in the numbers of non-metastatic and metastatic nodes that were colored black. Of the 200 patients, 61 (30.5%) had microscopic evidence of metastatic lymph nodes. These 61 patients were divided into four groups according to the number of metastatic lymph nodes (Table 3). Five-year survival rates were 93.1% in patients without lymph node metastasis, 71.9% in patients with 1-3 metastatic lymph nodes, 36.1% in patients with 4-9 nodes and 19.2% in patients with >9 metastatic nodes. There were statistically significant differences in survival between the groups with no lymph node metastases and those with 1-3 metastatic nodes and between the groups with 1-3 metastatic lymph nodes and those with 4-9 (Fig. 1). Five-year survival rates according to the anatomical extent of lymph node metastases were 93.1% in n0 (n = 139), 63.1% in n1 (n = 23), 37.9% in n2 (n = 25), 27.8% in n3 (n = 9) and 0% in n4 (n = 4). Statistically significant differences were observed only between n0 and n1 subjects (Fig. 2). The number of metastatic lymph nodes was identified by multivariate analysis as an independent prognostic factor for survival in gastric cancer, in addition to the anatomical extent of metastatic lymph nodes (Table 4).

Table 1. Relationship between the anatomical level of lymph node dissection and mean numbers of dissected nodes per patient

Study	Level of lymph node dissection	No. of cases	No. of lymph nodes dissected
This work	D1	n = 27 (15.0%)	32.5
	D2,3	n = 131 (72.8%)	42.3
	D4	n = 22 (12.2%)	66.3
Manzoni et al. (15)	D1	n = 65 (40.1%)	18.2
	D2	n = 59 (36.4%)	31.3
	D4	n = 38 (23.5%)	47.0

Table 2. Proportion of lymph nodes colored black by CH40

	No. of blackened lymph nodes/No. of dissected lymph nodes
Non-metastatic lymph nodes	3391/7996 (42.4%)
Metastatic lymph nodes	192/513 (37.4%)
Total	3581/8507 (42.1%)

Differences were not statistically significant.

Table 3. Relationship between the number of metastatic lymph nodes and number of cases

Study	No. of metastatic lymph nodes	No. of patients
This work	1-3	22 (36.1%)
	4-9	19 (31.1%)
	>9	20 (32.8%)
Isozaki et al. (5)	1-4	187 (56.7%)
	5-10	80 (24.2%)
	>10	63 (19.1%)
Ichikura et al. (15)	1-5	150 (47.8%)
	6-10	67 (21.3%)
	>10	97 (30.9%)

Table 4. Multivariate analysis to identify independent prognostic factors for survival of surgically treated gastric cancer patients

Variable	Standardized regression coefficient	p value
Depth of cancer invasion	1.187	0.000
No. of metastatic LN	0.522	0.003
Histology	0.498	0.023
Age	0.252	0.238
Gender	0.185	0.318
Level of LN dissection	0.015	0.931
Depth of cancer invasion	1.022	0.001
Anatomical extent of LN	0.635	0.002
Histology	0.593	0.014
Age	0.319	0.175
Level of LN dissection	0.029	0.869
Gender	0.011	0.956

LN: lymph nodes.

DISCUSSION

When injected into tissues, particles of CH40 are absorbed into lymph vessels and reach regional lymph nodes; they are not adsorbed by blood vessels. Lymph nodes containing CH40 become blackened and are easily identified by the naked eye, even when they are very small. These properties permit CH40 to be used as a clear marker during lymph node dissection (8-11) and enable a larger number of lymph nodes to be dissected than in patients where the technique of CH40 injection has not been employed. This is particularly valuable for identifying distant regional lymph nodes, e.g. para-aortic nodes. In this study, the average number of dissected lymph nodes was 32.5 in the patient who underwent Dl dissection, 42.3 in D2,3 and 66.3 in D4. Another report has quoted average numbers of dissected lymph nodes as 18.2 per patient in Dl (n = 65), 31.3 in D2 (n = 59) and 47.0 in D4 (n = 38) (15). We dissected more lymph nodes at this level of dissection than in any other studies (Table 1). This is probably due to the markedly increased peroperative visibility of lymph nodes in even very small ones after visualization with the CH40 injection technique.

There was no significant difference between the numbers of blackened metastatic and non-metastatic lymph nodes (Table 2). This indicates that metastatic lymph nodes have an intact lymphatic system allowing CH40 to reach them as efficiently as non-metastatic nodes. Using preoperative endoscopic injection of carbon particles into the gastric mucosa, the proportion of blackened lymph nodes found subsequently at operation was 68.8% on average (10). In contrast, intra-operative intra-nodal injections of CH40 resulted in a lower uptake in lymph nodes (42.1%; 3583/8509). This was because only one node near the tumor was injected during the peroperative procedure, whereas uptake in almost all the regional lymph nodes will have resulted from injection into the gastric mucosa.

Figure 1. Five-year survival rates according to the number of metastatic lymph nodes. 0, No lymph node metastasis; 1-3, one to three metastatic lymph nodes; 4-9, four to nine metastatic lymph nodes; >9, more than nine metastatic lymph nodes. Values in parentheses are percentages surviving five years. *P < 0.05.

Figure 2. Five-year survival rate according to the nodal classification stage rule of JRSGC. n0, No lymph node metastasis; n1, lymph node metastasis in compartment 1; n2, lymph node metastasis in compartment II; n3, lymph node metastasis in compartment III; n4, lymph node metastasis in compartment IV. Values in parentheses are percentages surviving 5 years. *P < 0.01.

Between four and nine metastatic lymph nodes were found in 19 patients (31.1%) and more than nine metastatic nodes in 20 patients (32.8%). Using the current technique of intra-nodal injection of CH40, the proportion of patients with a large number of metastatic lymph nodes, e.g. 4-9 and >9, was higher than in other reports (5,16) (Table 3). This suggests that blackening lymph nodes with CH40 allows a larger number of smaller nodes to be identified, even those that are not obvious to the naked eye.

Figure 3. Five-year survival rate according to the new TNM classification. N0, No lymph node metastasis; N1, 1-6 metastatic lymph nodes; N2, 7-15 metastatic lymph nodes; N3, >16 metastatic lymph nodes. Values in parentheses are percentages surviving 5 years. *P < 0.001; **P < 0.05.

In this study, with regard to our cases who received injection of CH40, a larger number of metastatic lymph nodes was associated with a poorer prognosis. Other reports have come to similar conclusions (17-19). We divided the classification according to the number of metastatic lymph nodes into four groups, viz. patients without lymph node metastasis and those with 1-3, 4-9 and >9 metastatic lymph nodes. In our study, this classification reflected most closely the prognosis of gastric cancer according to the number of metastatic lymph nodes. Although our data were analyzed according to the new TNM classification, our classification provided better results than the new TNM classification. According to the new TNM classification, there was no difference between N1 and N2 of our data (Fig. 3). Since small-sized metastatic lymph nodes were found by injection of CH40, some patients of the N2 stage in our study were candidates for patients of the N1 stage during the usual analysis. The patients of the N1 stage, who had an essentially good prognosis, migrated to the N2 stage on injecting CH40. This may be one of the reasons why there was no difference between N1 and N2 of our data. If injections of CH40 were performed routinely, it may produce a new category of classification according to the number of metastatic lymph nodes. On the other hand, in the current study the anatomical extent of metastatic lymph nodes using the JRSGC rule was also associated with progressively poorer 5-year survival. Thus, not only the number of metastatic lymph nodes but also their anatomical extent were factors which were independently associated with poor prognosis in gastric cancer. Since both are independent prognostic factors, the number of lymph node metastases is sufficient for the purpose of identification of prognosis. However, the number of metastatic lymph nodes cannot express the curability of surgical resection for gastric cancer. Therefore, the anatomical extent of lymph node metastasis and the D number (the level of lymph node dissection) are indispensable for the purpose of curability and education on surgical techniques according to the extent of gastric cancer. In conclusion, both the number of metastatic lymph nodes and their anatomical extent identified by intra-operative lymph node injection of CH40 were closely related to the prognosis of patients with gastric cancer.

Acknowledgment

This study was presented and received an award as excellent work at the 27th Japanese Society for Cancer and Lymph Node Research (Kyoto, October 1997).

References

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Received June 17, 1998; accepted November 2, 1998
For reprints and all correspondence: Kazuma Okamoto, First Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail: okamoto{at}1surg.kpu-m.ac.jp

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