Japanese Journal of Clinical Oncology 31:495-499 (2001)
© 2001 Foundation for Promotion of Cancer Research
Risk Factors for Lymph Node Metastases and their Prognostic Significance in Early Gastric Cancer (EGC) for the Italian Research Group for Gastric Cancer (IRGGC)
1U. O. di Chirurgia Toracica, Ospedale G. B. Morgagni, Forlì, 2U. O. di Chirurgia Generale 1, Ospedale G .B. Morgagni, Forlì, 3Istituto di Scienze Chirurgiche, Università di Siena, Siena, 4Istituto di Semeiotica Chirurgica, Università di Verona, Verona, 5Servizio di Anatomia Patologica, Ospedale L. Pierantoni, Forlì and 6Istituto Oncologico Romagnolo di Forlì, Forlì, Italy
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Background: Lymph node metastases are present in only about 15% of patients with early gastric cancer (EGC) and for this reason, the majority of these patients do not require lymphadenectomy. In Japan, EGC patients undergo less invasive treatment (endoscopic mucosal resection, wedge resection, laparoscopy). However, the indications for and results of these types of treatment are still uncertain.
Methods: In a multicentre retrospective study, we analysed the clinicopathological data referring to 584 early gastric cancer patients who underwent D2 gastrectomy. A comparison was made between patients with and without lymph node metastases in relation to numerous pre- and postoperative variables. Long-term survival and risk factors for lymph node metastases were analysed. The primary aim was to compare our results with those of Western and Japanese authors; we also evaluated the possibility of identifying a subset of patients at low risk of lymph node metastases who may be candidates for endoscopic treatment.
Results: The incidence of lymph node metastasis was 14.4%. Univariate and multivariate analyses showed that submucosal infiltration, diffuse histotype, tumour size and Kodama Pen A type were all related to the presence of lymph node metastases. Patients with types I, IIa and IIb mucosal tumours did not present lymph node metastases. Postoperative mortality was 2.2%. Five-year survival in relation to lymph node groups was 95% in N0 patients, 77% in N1 patients and 60% in N2 patients (p = 0.0001, Japanese N-stage). The number of positive lymph nodes also had a prognostic value. Patients with three or fewer positive lymph nodes presented a better 5-year prognosis (83%) than those with more than three positive lymph nodes (48%) (p = 0.0001).
Conclusions: Our study confirms that lymph node involvement is an extremely important prognostic factor. For this reason, the therapeutic strategy of our surgical units is as follows: 1) D2 gastrectomy is the standard treatment even in early gastric cancer (EGC); 2) endoscopic mucosal resection (EMR) could be considered first in types I, IIa and IIb tumours that are diagnosed as limited to the mucosal layer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Prognosis is generally favourable in early gastric cancer (EGC) when treated surgically, with a 5-year survival of more than 90%, as confirmed in both Japanese and Western studies (1–5).
The most important prognostic factor is undoubtedly metastatic lymph node involvement, the incidence of which ranges from 10 to 42% (1,2,6,7), with an average value of 15%. It therefore follows that about 85% of patients undergo unnecessary lymphadenectomy.
Preoperative staging, including endoscopic ultrasonography, is not specific enough to identify the presence of lymph node metastases (8). Only a retrospective examination of clinicopathological data obtained from patients previously treated for EGC is predictive of metastatic lymph node involvement. The present retrospective study analyses data referring to 584 patients operated on for EGC and focuses in particular on risk factors for lymph node metastases.
The aim of the present study was to compare our results with those of Western and Japanese authors and then evaluate the possibility of identifying a subset of patients at low risk of lymph node metastases who may be candidates for endoscopic treatment.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Five hundred and eighty-four patients were operated on for EGC at three Surgical Units (Divisione di Chirurgia 1, G. B. Morgagni Hospital, Forlì, Istituto di Semeiotica Chirurgica, University of Verona and Istituto di Scienze Chirurgiche, University of Siena) during the period 1976–97. Subtotal gastrectomy was carried out for tumours located in the lower two-thirds of the stomach and total gastrectomy for tumours in the upper third. Both surgical procedures were completed by level I (N1) and II (N2) lymphadenectomy (according to the JRSGC classification) (9). Lymph node metastases were classified as N0, N1 or N2 according to the Japanese system.
Macroscopic classification was carried out in accordance with the criteria of the Japanese Society of Gastroenterologic Endoscopy. Histological type and epithelium of origin were designated according to Lauren’s classification (10) and multifocality was defined according to Moertel’s criteria (11). Furthermore, patients were classified by the pathologist according to the Kodama classification (12), which evaluates tumour growth and development.
Kodama classifies EGC as follows: Super (superficial spreading) type, designated as a lesion having a diameter of >4 cm and confined to the mucosa (Super M) or with a slight invasion of the submucosa (Super SM); small mucosal type, a carcinoma with a diameter of <4 cm, with (Small mucosal SM) or without slight submucosal invasion (Small mucosal M); Pen (penetrating) type, a lesion with a diameter of <4 cm that has invaded the submucosa in a wide penetrating fashion. This type is further divided into two subtypes, according to the mode of invasion through the muscularis mucosae: Pen A type, invading expansively with complete destruction of muscularis mucosae, and Pen B type, growing infiltratively with fenestration of muscularis mucosae; mixed type represents a small number of tumours having growth patterns of both Super and Pen types, that is, a lesion >4 cm with massive invasion of the submucosa.
Patients were seen on average every 6 months for the first 5 years and thereafter once per year. Long-term survival was calculated from the date of surgery. Only deaths due to EGC were considered. Deaths due to other causes, included postoperative mortality, were censored at the date of death.
The study of the association between lymph node metastases and other clinicopathological variables was conducted using the chi-squared test in univariate analysis and the multiple logistic regression model in multivariate analysis where tumour size was considered as a continuous variable.
The survival curve in function of lymph node status was traced using the Kaplan–Meier method (13). The difference between curves was tested using the log-rank test (14).
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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The 584 patients who underwent surgery represent 25% of the total number of patients treated for gastric cancer in the same period. Metastatic lymph node involvement was present in 84 patients (14.4%): 63 (10.7%) were classified as N1 and 21 (3.5%) as N2. Mucosal type cancer presented lymph node involvement in 3.7% of cases, in contrast to 25.3% of submucosal forms. The mean number of positive lymph nodes was 2 (range 1–29). The number of positive lymph nodes was
3 in 62 patients and >3 in 22. Table 1 shows the clinicopathological factors in relation to the presence or absence of lymph node metastases.
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The diameter of the neoplasm was significantly greater and submucosal infiltration was more frequent in patients with lymph node metastases (p < 0.001). The diffuse histological type showed a high incidence of lymph node metastases (p < 0.001) and Kodama Pen A type more frequently involved lymph nodes than other Kodama types (p < 0.001).
When a stratified analysis of different variables with respect to the lymph node involvement was conducted, we observed that polypoid types I and IIa and flat type IIb, with mucosal involvement, did not develop lymph node metastases, independently of tumour dimensions and histological type. The above characteristics were found in 71 of our patients. In these patients, the tumour was localized in the upper third of the stomach in nine cases, the middle third in 23 cases and lower third in 39 cases.
Furthermore, all clinicopathological factors were evaluated by logistic regression analysis. Independent risk factors for lymph node metastases were as follows: submucosal invasion, Kodama Pen A type, diffuse histotype and tumour dimensions (Table 2).
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Postoperative mortality was 2.2% (13 patients) and morbidity was 14.4% (84 patients). In the last decade, postoperative mortality has decreased to 1.3%. The mean follow-up duration was 8 years. One patient was lost to follow-up and was therefore excluded from the study. The 5-year survival rate of patients with negative lymph nodes (N–) was 95% (95% CI = 93–97), whereas that of node positive patients (N+) was 73% (95% CI = 62–84) (Fig. 1).
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The 5-year survival rate in positive lymph node groups was 77% for N1 patients (95% CI = 65–89) and 60% for N2 patients (95% CI = 37–83) (Fig. 2).
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The number of positive lymph nodes was also a prognostic factor; patients with
3 positive lymph nodes presented a better 5-year survival [83% (95% CI = 72–93)] than those with 
4 lymph node metastases [48% (95% CI = 25–71)] (Fig. 3).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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Gastrectomy with lymph node dissection is the most widespread surgical procedure used in the treatment of EGC both in Japan and Western countries (1,3,4,6,7,9,15). However, in Western reports there have been very few cases homogeneous or not as regards level of lymphadenectomy.
Here we found a 14.4% incidence of lymph node metastases, similar to that indicated by other authors (1,5). Kitamura et al. (5) reported an average of 2.64 positive lymph nodes per patient, which is similar to our own experience of 2.0 lymph nodes per patient.
Our results show that intramucosal carcinoma infiltrated lymph nodes in only 3.7% of cases, which is in agreement with data presented by Yamao et al. (16) and Tsujitani et al. (17). In contrast, submucosal carcinoma had a 25.3% lymph node involvement, which is higher than that reported by Kurihara et al. (18) and Kitamura et al. (5), but similar to that described by Ohta et al. (6) and Sowa et al. (19).
The distribution of I and II level lymph node metastases in our series was 10.7 and 3.5%, respectively, which matches data reported in the Japanese literature (19,20).
The 2.2% hospital mortality is similar to that observed by other Western centres (21,22), but higher than that by Japanese authors (1,15). This is probably due to the fact that in Japan there are surgeons with wide experience in gastric surgery, which obviously helps to improve results. Looking at our own series of patients over the past 10 years, it can be seen that experience has undoubtedly lowered postoperative mortality (1.3%).
The presence of lymph node metastases (N+) in EGC worsens prognosis, as reported by Kitamura et al. (5), Maehara et al. (1) and Katai et al. (23) and as observed in our study. Nio et al. (24) reported for EGC a 5-year survival of 93% for N1 patients and 68.4% for N2 patients and Miwa (25) observed similar rates of 90 and 79%, respectively.
According to the old TNM classification (26), Katai et al. (23) observed that for patients with N1 and N2 involvement, the 5-year survival is 91%.
Seto et al. (20) reported a 5-year survival of 74% for patients with >4 positive lymph nodes. Our series had a substantially lower 5-year survival, especially as regards N2 patients (60%) and patients who presented >3 metastatic lymph nodes (48%). The poor prognosis of our N2 patients can probably be attributed to the smaller case series than those of Japanese authors. Furthermore, some N2 patients with >3 metastatic lymph nodes may have been understaged (we do not perform D3 gastrectomy for EGC).
Univariate analysis showed that lymph node metastases were significantly associated with large tumours, submucosa-infiltrating lesions, diffuse histotype and Pen A type according to Kodama (Table 1). Maehara et al. (1) observed that independent risk factors for lymph node metastases are large tumour dimension, lymphatic involvement and submucosal invasion. Yamao et al. (16) also reported that lymphatic invasion, the histological ulceration of the tumour and larger tumor size are independent risk factors for lymph node metastases of intramucosal EGC.
In the present series, multivariate analysis showed that the risk of lymph node metastasis was associated with submucosal infiltration, tumour size and diffuse histotype (Table 2). Kodama Pen A type was also observed as an independent risk factor in relation to the growing characteristics of the tumour, which invades the submucosa expansively, completely destroying the muscularis mucosae.
Sano et al. (27) reported that tumours with the following characteristics generally do not metastasize to lymph nodes: (1) mucosal infiltration, (2) tumour dimension of <1.5 cm in diameter, (3) elevated macroscopic type, (4) depressed macroscopic type without ulceration or ulcer scar and (5) histologically differentiated type. In our series, the 71 patients who had mucosal tumours and macroscopic type I, IIa or IIb did not present lymph node metastases, regardless of tumour dimension and histotype.
Several authors (1,17,18,28,29) have concluded that D2 gastrectomy is indicated when EGC presents with large tumour dimension and invasive characteristics. In our experience, it is possible to determine tumour size and histotype perioperatively, but difficult to obtain accurate information on the degree of submucosal invasion.
The introduction of endoscopical ultrasonography with 20 MHz probes has undoubtedly improved diagnostic accuracy, but unfortunately it still remains far from satisfactory (30).
Sano et al. (27) and Yamao et al. (16) stated that it is necessary to examine the whole resected lesion in order to confirm whether the tumour is confined to the mucosa. The ‘strip biopsy’ or endoscopical mucosal resection (EMR), proposed by Tada et al. (31), can, in some cases, achieve this objective. Yamao et al. (16) maintained that, in patients with intramucosal EGC without risk factors for lymph node metastasis, EMR should be considered not only as a diagnostic procedure but also a radical treatment.
In contrast, Baba et al. (15) and Siewert et al. (32) claimed that D2 lymphadenectomy also improves prognosis in patients without lymph node metastases (N0), the reason being that the micrometastases present in about 10% of cases can only be detected with immunohistochemical techniques that are not routinely used.
Noda et al. (33) believe that endoscopic treatment is a useful approach in a limited number of cases because conventional surgery has an extremely high 5-year survival rate (98%) that endoscopic treatment has yet to achieve.
Our experience confirms these data and we also observe good long-term survival, but dependent on the number of metastatic lymph nodes (4,34).
On the basis of our results, we conclude that (1) even in EGC, D2 gastrectomy should be considered the standard treatment where it can be safely performed; and (2) lesions diagnosed as mucosal cancer type I, IIa or IIb should first be treated by EMR. If histological examination of the EMR specimen reveals that there is submucosal invasion, D2 gastrectomy should be performed.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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We thank Ms G. Tierney and Ms M. Basso for their assistance. This paper was presented at the 3rd International Gastric Cancer Congress, Seoul, Korea, April 27–30, 1999.
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FOOTNOTES |
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+ For reprints and all correspondence: Secondo Folli, U. O. di Chirurgia Toracica, Ospedale G. B. Morgagni, P.le Solieri 1, 47100 Forlì, Italy
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentsREFERENCES |
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1 Maehara Y, Orita H, Okuyama T, Moriguchi S, Tsujitani S, Korenaga D, et al. Predictors of lymph-node metastasis in early gastric cancer. Br J Surg 1992;79:245–7.[Web of Science][Medline]
2 Habu H, Takeshita K, Sunawaga M, Endo M. Lymph node metastases in early gastric cancer. Int Surg 1986;71:244–7.[Web of Science][Medline]
3 Guadagni S, Reed PI, Johnston BJ, De Bernardinis G, Catarci M, Valenti M, et al. Early gastric cancer: follow up after gastrectomy in 159 patients. Br J Surg 1993;80:325–8.[Web of Science][Medline]
4 Folli S, Dente M, Dell’Amore D, Gaudio M, Nanni O, Saragoni L, et al. Early gastric cancer: prognostic factor in 223 patients. Br J Surg 1995;82:952–6.[Web of Science][Medline]
5 Kitamura K, Yamaguchi T, Taniguchi M, Hagiwara A, Sawai K, Takahashi T. Analysis of lymph node metastasis in early gastric cancer: rationale of limited surgery. J Surg Oncol 1997;64:42–7.[Web of Science][Medline]
6 Ohta H, Noguchi Y, Takagi K, Nishi M, Kajitani T, Kato Y. Early gastric carcinoma with special reference to macroscopic classification. Cancer 1987;60:1099–106.[Web of Science][Medline]
7 Hayes N, Karat D, Scott DJ, Raimes SA, Griffin SM. Radical lymphadenectomy in the management of early gastric cancer. Br J Surg 1996;83:1421–3.[Web of Science][Medline]
8 Akahoshi K, Chijiiwa Y, Hamada S, Sasaki I, Maruoka A, Kabemura T, et al. Endoscopic ultrasonography: a promising method for assessing the prospects of endoscopic mucosal resection in early gastric cancer. Endoscopy 1997;29:614–9.[Web of Science][Medline]
9 Japanese Research Society for Gastric Cancer. Japanese Classification of Gastric Carcinoma, 1st Engl. Ed. Tokyo: Kanehara 1995.
10 Lauren P. The two histological main types of gastric carcinoma: diffuse and so-called intestinal type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965;64:31–49.[Web of Science][Medline]
11 Moertel CG, Bargen JA, Soule EH. Multiple gastric cancer. Review of the literature and study of 42 cases. Gastroenterology 1957;32:1095–103.[Web of Science][Medline]
12 Kodama Y, Inokuchi K, Soejima K, Matsusaka T, Okamura T. Growth patterns and prognosis in early gastric cancer. Superficially spreading and penetrating growth types. Cancer 1983;51:320–6.[Web of Science][Medline]
13 Kaplan EL, Meier P. Non parametric estimation from incomplete observation. J Am Stat Assoc 1958;53:457–81.[Web of Science]
14 Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;50:163–70.[Medline]
15 Baba H, Maehara Y, Takeuchi H, Inutsuka S, Okuyama T, Adachi Y, et al. Effect of lymph node dissection on the prognosis in patients with node negative early gastric cancer. Surgery 1994;117:165–9.
16 Yamao T, Shirao K, Ono H, Kondo H, Saito D, Yamaguchi H, et al. Risk factors for lymph node metastasis from intramucosal gastric carcinoma. Cancer 1996;77:602–6.[Web of Science][Medline]
17 Tsujitani S, Oka S, Saito H, Kondo A, Ikeguchi M, Maeta M, et al. Less invasive surgery for early gastric cancer based on the low probability of lymph node metastasis. Surgery 1999;125:148–54.[Web of Science][Medline]
18 Kurihara N, Kubota T, Otani Y, Ohgami M, Kumai K, Sugiura H, et al. Lymph node metastasis of early gastric cancer with submucosal invasion. Br J Surg 1998;85:835–9.[Web of Science][Medline]
19 Sowa M, Kato Y, Nishimura M, Kubo T, Maekawa H, Umeyama K. Surgical approach to early gastric cancer with lymph node metastasis. World J Surg 1989;13:630–6.[Web of Science][Medline]
20 Seto Y, Nagawa H, Muto T. Impact of lymph node metastasis on survival with early gastric cancer. World J Surg 1997;21:186–90.[Web of Science][Medline]
21 Jentschura D, Heubner C, Manegold BC, Rumstadt B, Winkler M, Trede M. Surgery for early gastric cancer: a European one center experience. World J Surg 1997;21:845–8.[Web of Science][Medline]
22 Pertl A, Jagoditsch M, Jatzko GR, Denk H, Stettner H. Long term results of early gastric cancer accomplished in a European institution by Japanese-type radical resection. Gastric Cancer 1999;2:115–21.[Medline]
23 Katai H, Yoshimura K, Maruyama K, Sasako M, Sano T. Evaluation of the new international union against cancer TNM staging for gastric carcinoma. Cancer 2000;88:1796–800.[Web of Science][Medline]
24 Nio Y, Tsubono M, Kawabata K, Masai Y, Hayashi H, Meyer C, et al. Comparison of surgical curves of gastric cancer patients after surgery according to the UICC stage classification and the general rules for gastric cancer study by the Japanese Research Society for Gastric Cancer. Ann Surg 1993;218:47–53.
25 Miwa K, Japanese Research Society for Gastric Cancer. Evaluation of the TNM classification of stomach cancer and proposal for its rationale stage-grouping. Jpn J Clin Oncol 1984;14:385–410.
26 Sobin LH, Wittekind CH, editors. TNM Classification of Malignant Tumors. International Union Against Cancer, 5th ed. New York: Wiley 1997.
27 Sano T, Kobori O, Muto T. Lymph node metastasis from early gastric cancer: endoscopic resection of tumor. Br J Surg 1992;79:41–4.
28 Nakamura K, Morisaki T, Sugitani A, Ogawa T, Uchiyama A, Kinukawa N, et al. An early gastric carcinoma treatment strategy based on analysis of lymph node metastasis. Cancer 1999;85:1500–5.[Web of Science][Medline]
29 Takekoshi T, Baba Y, Ota H, Kato Y, Yanagisawa A, Takagi K, et al. Endoscopic resection of early gastric carcinoma: result of a retrospective analysis of 308 cases. Endoscopy 1994;26:352–8.[Web of Science][Medline]
30 Yanai H, Matsumoto Y, Harada T, Nishiaki M, Tokiyama H, Shigemitsu T, et al. Endoscopic ultrasonography and endoscopy for staging depth of invasion in early gastric cancer: a pilot study. Gastrointest Endosc 1997;46:212–6.[Web of Science][Medline]
31 Tada M, Shimada M, Murakami F, Karita M. Development of the strip off biopsy. Gastroenterol Endosc 1984;26:833–9.
32 Siewert JR, Kestlmeier R, Bush R, Botteher D, Roder JD, Muller J, et al. Benefits of D2 lymph node dissection for patients with gastric cancer and pN0 and pN1 lymph node metastasis. Br J Surg 1996;83:1144–7.[Web of Science][Medline]
33 Noda M, Kodama T, Atsumi M, Nakajima M, Sawai N, Kashima K, et al. Possibilities and limitation of endoscopic resection for early gastric cancer. Endoscopy 1997;29:361–5.[Web of Science][Medline]
34 De Manzoni G, Verlato G, Guglielmi A, Laterza E, Genna M, Cordiano C. Prognostic significance of lymph node dissection in gastric cancer. Br J Surg 1996;83:1604–7.[Web of Science][Medline]
Received March 6, 2001; accepted July 5, 2001.
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