Japanese Journal of Clinical Oncology 33:209-214 (2003)
© 2003 Foundation for Promotion of Cancer Research
Clinicopathological Analysis for Recurrence of Early Gastric Cancer
1 Department of Surgery, 2 Department of Surgery and Cancer Research Institute and 3 Department of Pathology and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Although the prognosis of early gastric cancer (EGC) is considered to be satisfactory, some patients experience disease recurrence after curative resection. This study was aimed at evaluating the recurrence rate, the recurrence patterns and the prognostic factors for recurrence of EGC as well as treatment results after recurrences.
Methods: We investigated follow-up records of 1452 EGC patients on whom curative operations were performed at Seoul National University Hospital from 1986 to 1995 with special reference to cancer recurrence.
Results: Twenty-one patients showed recurrences with a 1.5% 5-year cumulative recurrence rate. Four cases were locoregional recurrences, two were peritoneal recurrences, nine were distant recurrences and six were mixed type recurrences. The 5-year survival rates of T1N0, T1N1, T1N2 and T1N3 were 99.3, 96.8, 72.7 and 0%, respectively (P < 0.001). Multivariate analysis revealed a significantly high correlation between positive lymph node metastasis and recurrence (P < 0.001). Median survival after recurrence of EGC was 4.3 months. Median survival after recurrence was 5.8 months after chemotherapy and 3.1 months after conservative management (P = 0.69).
Conclusion: Although the recurrence of EGC is very rare in general, EGC with lymph node metastasis has a higher possibility of recurring, especially with >6 positive lymph nodes. Even after curative resection of EGC, patients with EGC with >6 positive lymph nodes should be closely followed and be considered as candidates for adjuvant treatment.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The detection rate of early gastric cancer (EGC) has been increasing owing to the development of diagnostic procedures such as endoscopy and double contrast roentgenography. The diagnosis of EGC in Japan has progressively increased, in part owing to mass screening, and these patients account for 40–50% of operations carried out for gastric carcinoma (1). In Korea, the proportion of EGC patients is increasing, although it has not reached the Japanese level. According to a recent report of the Korean Gastric Cancer Association (2), the proportion of EGC increased from 28.6% in 1995 to 32.8% in 1999. The prognosis of patients with EGC is very favorable after curative gastrectomy with lymph node dissection. The 5- and 10-year survival rates for patients with EGC are more than 90 and 85–90%, respectively (3,4). However, it has been reported that recurrence of EGC occurred in some patients after curative gastric resection (5,6). The recurrence of advanced gastric cancer has been examined in many other reports and depth of invasion and lymph node metastasis are thought to be the most important risk factors. However, in EGC, little has been evaluated about the recurrence rate, the recurrence patterns and the prognostic factors for recurrence because of the relatively low incidence of recurrence after curative resection for EGC. Furthermore, the treatment results for recurrence of EGC have rarely been studied until now.
The aim of this study was to evaluate the recurrence rate, the recurrence patterns and the prognostic factors for recurrence of EGC and also treatment results after recurrences.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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For recurrence analysis, we analyzed the clinicopathological features of 1452 EGC patients who underwent curative gastrectomy at Seoul National University Hospital between 1986 and 1995. All patients underwent a gastrectomy with sufficient lymph node dissection to the D2 level in accordance with the General Rules for the Gastric Cancer Study of the Japanese Research Society for Gastric Cancer (7). Their clinicopathological features are shown in Table 1.
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Histopathological examinations were performed on the primary lesions using serial sections to determine the depth of cancer invasion and other histopathological features and on the resected lymph nodes using three central sections to confirm the presence of metastasis. All resected regional lymph nodes were subjected to histopathological examination. According to the 5th UICC–TNM classification for staging of gastric cancer, carcinomas without lymph node metastases were grouped as N0, those with 1–6 metastatic lymph nodes as N1, 7–15 nodes as N2 and >15 nodes as N3.
After being discharged from the hospital, the patients were entered into a regular follow-up program with gastrofiberoscopy, barium meal study, ultrasonography, computed tomography or combination of these modalities every 6 months for the first 5 years and thereafter at intervals of 12 months. The clinical records, the database of the national statistical office based on vital registration and telephone interviews were used for vital status investigation. The number of patients lost to follow-up was 38 (2.6% follow-up loss rate) and the median follow-up period was 57.7 months. Five cases of gastric cancers were found in the remnant stomach during the follow-up. All these were regarded as metachronous primary cancer and were excluded from the recurrence analysis.
The recurrence of disease was confirmed by physical findings, radiological studies, endoscopic examination with biopsy and surgery. The patterns of recurrence were classified into four types: locoregional recurrence of perigastric lymph nodes; distant recurrence to liver, lung, brain and distant lymph nodes; peritoneal recurrence including Krukenberg’s tumor; and mixed type of recurrence.
The Kaplan–Meier method was used to estimate survival rates and differences between them were assessed with the log-rank test. Multivariate analysis was performed using the Cox proportional hazards model. A P-value of <0.05 was considered to be statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Clinicopathological Analysis of Recurrent Cases (Table 2)
Twenty-one patients (1.5% 5-year cumulative recurrence rate) out of the 1452 who had undergone curative gastrectomy between 1986 and 1995 had recurrences. In these recurred cases, submucosal invasion was present in 16 cases (76.2%) and lymph node metastasis was positive in 14 cases (66.7%) at the time of operation. Among these node-positive patients, there were six patients with <6 positive nodes (N1), six with 7–15 (N2) and two with >16 (N3). The median interval between gastrectomy and recurrence was 18.5 months. Thirteen cases (61.9%) recurred within 24 months (early recurrence), six cases (28.6%) recurred between 24 and 60 months and late recurrence after 60 months occurred in two cases (9.5%).
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Pattern and Site of Recurrence (Table 2)
Twenty-one cases of recurrence included four (19.0%) with locoregional recurrence, two (9.5%) with peritoneal dissemination, nine (42.9%) with distant metastasis and six (28.6%) with mixed type recurrence.
Locoregional Recurrence
In the four cases of local lymph node recurrence, two cases had perigastric lymph node metastasis at the time of primary operation. The time intervals between primary operation and recurrence were 1.5 and 18.5 months in N0 cancers and 7.3 and 18.0 months in N1 cancers.
Peritoneal Recurrence
Two cases with peritoneal recurrences were diagnosed by cytological examination of ascites which had been detected by abdominal computed tomography. Both cases had lymph node metastases at the time of primary operation. The time intervals between primary operation and recurrence were 3.0 and 9.5 months.
Distant Recurrence
In the nine cases of distant metastasis, seven were multiple metastases and two were liver and cervical lymph node metastases. These cases included two N0 stages, three N1 stages, three N2 stage and one N3 stage at the time of primary operation.
Mixed Recurrence
In the six cases of mixed recurrences, four were loco-distant recurrences, one was loco-peritoneal recurrence and one was peritoneo-distant recurrence. There included three N0 stages, two N1 stages and one N2 stage at the time of primary operation.
Risk Factors of Recurrence
The recurrence rate was significantly higher with submucosal cancer than with mucosal cancer (
2 = 6.02, 1 disease free (d.f.), P = 0.014) and higher with lymph node metastasis than without lymph node involvement (2 = 54.38, 1 d.f., P < 0.001). When lymph node status was subdivided according to N stage, 5-year disease-free survival rates of patients with N0, N1, N2 and N3 were 99.3, 96.8, 72.7 and 0%, respectively (2 =447.40, 3 d.f., P < 0.001) (Fig. 1). Age, gender, tumor size, macroscopic type and histological type were unrelated to the incidence of recurrence (Table 3). Multivariate analysis which was performed with significant factors identified by univariate analysis (depth of invasion, lymph node metastasis) demonstrated that lymph node metastasis was the only independent prognostic factor for recurrence (Table 4).
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For the recurrence patterns, no statistically significant prognostic factor concerning the recurrence pattern was found using univariate analysis.
Prognosis of Recurrent Cases
The median survival after recurrence was 4.3 months. The treatment modalities after recurrence were chemotherapy in six cases and conservative management in 15 cases. Median survival after recurrence was 5.8 months after chemotherapy and 3.1 months after conservative management and it was not statistically significant (P = 0.69).
Metachronous Gastric Cancer in Remnant Stomach (Table 5)
In the five cases of metachronous gastric cancers in the remnant stomach, there was no simultaneous cancer and there were sufficient tumor-free margins at the time of primary operation. There were two mucosal and three submucosal tumors without lymph node metastasis. The time intervals between primary operation and the diagnosis of metachronous cancer were 7, 23.5, 25.5, 70.5 and 88 months, respectively. All five patients underwent reoperations, including one total gastrectomy with splenectomy and four total gastrectomies. At the time of second operations, there were three T1 cancers and two T2 cancers and perigastric lymph node metastases were found in two cases. Median survival after reoperation was 46.8 months, with a tendency for longer survival than that for recurred patients although it was not statistically significant (P = 0.067).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Although the prognosis of EGC is excellent, a small but definite number of postoperative recurrences have been reported. The recurrence rate of EGC treated by D2 gastrectomy has been reported to vary from 1.4 to 6.4% (8–10). In our series, the recurrence rate for curative procedures was 1.5%.
For the recurrence patterns of EGC, most investigators have reported that the distant recurrence via hematogenous spread was the most common recurrence pattern. Shiozawa et al. (9) reported that about half of 20 patients with recurred EGC showed hematogenous recurrences. Folli et al. (11) also reported that 14 out of 22 recurred EGC cases showed hematogenous recurrences. Our study showed a similar result that distant recurrence was the most common pattern of recurrence (42.9%).
Interestingly, two out of four cases of local lymph node recurrence had no lymph node metastasis at the time of initial operation. One of the possible explanations for this finding is the concept of micrometastasis. Maehara et al. (12) reported that among 34 patients with node-negative EGC who died of a recurrence, eight were finally confirmed to have micrometastases using cytokeratin staining.
The hematogenous recurrence of EGC could be explained by the mechanism of lymphatic and vascular invasions during submucosal invasion of cancer cells (13). In mucosal cancer, a satisfactory explanation for hematogenous recurrence has not yet been suggested. In our study, seven out of nine distant recurrences had lymph node metastases at the time of initial operation and one had negative nodes with submucosal invasion and the other had negative nodes with mucosal invasion. Concerning peritoneal recurrence of early gastric cancer, a definite mechanism has not yet been elucidated. In our study, both of two cases of peritoneal recurrences had either lymph node metastasis or submucosal invasion, which suggests that the lymphatic invasion of cancer cells might have a role in peritoneal dissemination of EGC.
The risk factors related to recurrence of EGC have been discussed in several articles (14). Ichiyoshi et al. (8) reported that the elevated type, positive lymph node and invasion of lymphatic and venous vessels were significantly associated with a high risk of recurrence. Shiozawa et al. (9) considered some other factors, such as submucosal invasion, a gross appearance of IIa + IIc type and a tumor size >40 mm. In the present study, depth of invasion and lymph node metastasis were significant prognostic factors using univariate analysis. However, using multivariate analysis, lymph node metastasis was the only significant prognostic factor for the recurrence of EGC. Lymph node metastasis has been repeatedly proposed as one of the most important prognostic factors of EGC in many studies (15–17), similarly to our results.
This finding suggests that the treatment strategy of EGC with or without lymph node metastasis should be managed in different ways, including adjuvant chemotherapy. Chemotherapy in EGC with lymph node metastasis has been a controversial issue. Sano et al. (5) recommended that adjuvant chemotherapy for EGC with lymph node metastasis is not indicated because of its low frequency of recurrence, but Maehara et al. (12) supported adjuvant chemotherapy because of the high susceptibility of cancer cells within lymph nodes to chemotherapeutic agents. In the present study, the 5-year survival rates of T1N0, T1N1, T1N2 and T1N3 were 99.3, 96.8, 72.7 and 0%, respectively (Fig. 1). This result suggests that patients with EGC with >6 positive lymph nodes could be considered as a high risk group and candidates for adjuvant treatment such as chemotherapy.
It is well known that the management of recurred tumors is difficult owing to presence of extra-gastrointestinal lesions and combined type of recurrence. In our series, the median survival after recurrence was 4.3 months. Median survival after recurrence was 5.8 months after chemotherapy and 3.1 months after conservative management and it was not statistically significant. There were only three long-term survivors who had lived more than 1 year after recurrences.
There were five cases of metachronous cancers found in the remnant stomach during the follow-up period. All five cases were T1 or T2 cancers without distant lymph node metastasis, so reoperations for curable resection could be performed. Median survival after reoperation was 46.8 months, which showed a tendency for longer survival than that for recurred patients, although there was no statistical significance. Therefore, postoperative regular endoscopic follow-up could be considered as a useful method for early detection of metachronous gastric cancer in the remnant stomach.
In conclusion, although the recurrence of EGC is very rare in general, EGC with lymph node metastasis has a higher possibility of recurrence, especially with >6 positive lymph nodes. Even after curative resection of EGC, patients with EGC with >6 positive lymph nodes should be closely followed and be considered as candidates for adjuvant treatment.
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FOOTNOTES |
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+ For reprints and all correspondence: Han-Kwang Yang, Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110–744, Korea. E-mail: hkyang{at}plaza.snu.ac.kr
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Received November 27, 2003; accepted April 3, 2003
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