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Annals of Surgical Oncology 8:170-174 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Lymph Node Micrometastases in Patients With Early Gastric Cancer: Experience With 139 Patients

Paolo Morgagni, MD, Luca Saragoni, MD, Secondo Folli, MD, Michele Gaudio, MD, Emanuela Scarpi, MD, Francesca Bazzocchi, MD, Gian Angelo Marra, MD and Antonio Vio, MD

From the 1' Department of General Surgery (PM, FB, GAM, AV) and Thoracic Surgery (SF, GB) Morgagni Hospital; Anatomy and Pathology Service (LS, MG), L. Pierantoni Hospital; and the Romagnolo Oncology Institute (ES); Forlì, Italy.

Correspondence: Address correspondence and reprint requests to: Paolo Morgagni, MD, U.O. di Chirurgia Generale 1', Ospedale "G.B. Morgagni," P.le Solieri, 1-47100 Forlì, Italy; Fax: 0543-731260.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Although lymph node metastases in patients with early gastric cancer (EGC) is an important prognostic factor, the prognostic relevance of lymph node micrometastases is still uncertain.

Methods: The authors studied 1488 lymph nodes, which were histologically confirmed as pN0, dissected from 139 patients who were treated for EGC between 1976–1994. Micrometastases were defined as a single or small cluster of neoplastic cells identifiable only by immunohistochemical methods.

Results: Lymph node micrometastases was observed in 24 of the 139 patients (17%). No significant correlation was observed between micrometastases and other clinicopathological characteristics. Analysis of overall survival showed no significant difference between the micrometastases positive and negative groups.

Conclusion: The results of our study show that the presence of lymph node micrometastases in EGC does not have an influence on patient prognosis.

Key Words: Micrometastases • Lymphadenectomy • Early gastric cancer • Early gastric cancer prognosis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Prognosis for early gastric cancer (EGC) is mainly influenced by the presence of lymph node metastases which occur in 10–42% of cases, with a mean of 15%.1–4 The current therapeutic approach to treatment for patients with EGC is D2 gastrectomy and endoscopic mucosal resection for a subset of selected patients.

Siewert and Baba have reported that D2 lymphadenectomy improves long-term survival even in patients with no lymph node involvement (pN0).5,6 Siewert’s explanation of this is based on the presence of lymph node micrometastases that is identifiable only with immunohistochemical methods rather than traditional histological techniques. Micrometastasis removal by D2 lymphadenectomy guarantees a better long-term survival in these patients. To verify Siewert’s hypothesis, we conducted a retrospective study of 139 patients with EGC who underwent surgery and were found to be histologically staged pN0 by routine hematoxylin-eosin (H&E) staining. Our goal was to evaluate the incidence of micrometastases and the impact on long-term prognosis.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From 1976 to 1997, surgery was performed on 412 patients with EGC in the 1' General Surgery Department at G. B. Morgagni Hospital in Forlì, Italy. For this study, we assessed the first 139 patients (93 males, 46 females; mean age, 67 years) with pN0 lymph nodes as determined by H&E staining in the absence of distant metastasis (M0).

Subtotal gastrectomy was performed for tumors located in the lower two thirds of the stomach and total gastrectomy for tumors located in the upper one third of the stomach. Both interventions were completed by level I and II lymphadenectomies (D2) in accordance with the Japanese Classification of Gastric Carcinoma recommendations.7 This involved the en bloc resection of level I and II perigastric lymph nodes with the removal of the greater omentum, the upper leaf of the mesocolon, the pancreatic capsule, and the lesser omentum. A distance of more than 3 cm between the tumor and upper resection margin was maintained.

Macroscopic classification was made in accordance with the criteria of the Japanese Gastric Cancer Association,7 histological type was defined on the basis of Lauren’s classification,8 and multifocal lesions were classified according to Moertel et al.’s definiton.9 Type of tumor infiltration was subdivided according to Kodama et al.’s classification.10 Patients were seen every 6 months for the first 5 years and then once a year after that. Median follow-up was 9 years (range, 3–22). Survival was calculated from the date of surgery, and there was no postoperative mortality. Only cancer-related mortality was considered; other causes of mortality were considered as censored. None of the patients subsequently underwent complementary therapy.

All lymph nodes were sectioned on three levels at intervals of 150 µm and all sections were re-examined by two pathologists (MG and LS) for metastases identifiable with H&E staining. After that, the sections were tested with monoclonal antibodies directed against human cytokeratins (MNF 116, DAKO, Milan, Italy). Then they were deparaffinized using xylene, rehydrated in decreasing concentrations of alcohol, covered with rabbit serum for 15 minute to remove nonspecific staining, and then incubated with a primary antibody at room temperature for 1 hour. Antibody reaction was obtained using alkaline phosphatase conjugated with immunoglobulin.

Those lesions identified only by immunohistochemical techniques were considered as micrometastases. They were differentiated on the basis of the number of neoplastic cells and their aggregation (cluster) (Table 1).


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  		TABLE 1. Morphological Features of Lymph Node Micrometastases of EGC
 
Statistical analysis was carried out using SAS software (SAS Institute, Cary, NC). The {chi}2 test was used to evaluate the association between patients with and without micrometastases. Patient survival was analyzed using the Kaplan Meier product limit method,11 and the log rank test was used to evaluate the difference between the survival curves.12


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient characteristics are summarized in Table 2. A total of 1488 lymph nodes were examined, and preliminary reassessment confirmed the absence of metastases identifiable with H&E staining. Immunohistochemical techniques revealed the presence of micrometastases in 24 (17%) patients (15 males, 9 females). Single metastases was present in 22 patients, and 2 patients had two positive lymph nodes. Lymph node micrometastases were present in only 1.7% of all the lymph nodes dissected.


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  		TABLE 2. Patients With or Without Lymph Node Micrometastases as a Function of Clinical and Pathological Factors
 
Isolated neoplastic cells were found in 9 cases, multiple, nonaggregate neoplastic cells were found in several lymphatic sinuses of the same lymph node in 15 cases (Fig. 1), and in only 2 cases there were neoplastic cells in cluster (Fig. 2). All the micrometastases were sited in sub capsular lymphatic sinuses.



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  		FIG. 1. Neoplastic cells trapped within lymph node sinusoids. The cells show a positive intracytoplasmatic reaction for cytocheratins (MNF 116 immunostaining x 40).

 


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  		FIG. 2. Small group of neoplastic cells in a cortical lymph node sinus. Positive cells are stained diffusely throughout the cytoplasm (MNF 116 immunostaining x 20).

 
The frequency of patients with or without micrometastases was similar regardless of age, sex, tumor size, site of disease, macro- and microscopic type, depth of parietal infiltration, and type of infiltration according to Kodama (Table 2). The 5- and 10-year survival for patients with micrometastases, 87% [95% Confidence Interval (95% CI) = 71–100] and 87% [95% CI = 71–100], respectively, was not significantly different from that of patients without micrometastases, 88% [95% CI = 82–94] and 84% [95% CI = 77–91], respectively; log rank = 0.20, P = NS (Fig. 3).



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  		FIG. 3. Long-term survival curves for patients with positive (micro pos) and negative (micro neg) lymph node micrometastases.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Recently, numerous studies have been conducted on the incidence and significance of lymph node micrometastases in patients with neoplastic diseases. Although the definition of these lesions is generally widely accepted and currently defined as a single cell or small clusters of neoplastic cells identifiable only by means of immunohistochemical techniques, there is some disagreement about their incidence and prognostic impact.1,6,13–15

In colon cancer, the incidence of lymph node micrometastases for patients with Dukes’ stage A/B disease (without lymph node involvement) varies from 19% to 54%, with a mean of about 30%–35%.16–18 In breast cancer patients with histologically confirmed N0 nodes, the same incidence is 12%–20.6%,19,20 whereas non–small-cell lung cancer patients have a much higher incidence of micrometastases, ranging from 56.4%–70%.21,22

There is also some disagreement among published studies on the prognostic impact of micrometastases. In patients with colon cancer, Sasaki et al. and Liefers et al.18,23 report that the presence of micrometastases increases the risk of relapse, so affecting the prognosis, in contrast to other authors16,17,24,25 claims.

According to Troiani et al. and Clare et al.,19,26 long-term survival in patients with breast cancer seems to be influenced by the presence of micrometastases, whereas Kainz et al.27 claims that the small percentage of breast micrometastases reported in the literature does not modify patient survival. Elson et al.,20 after a 5.7 year follow-up, did not observe any difference in survival between breast cancer patients with or without micrometastases.

Conversely, the high incidence of micrometastases observed in lung cancer is always associated with a reduction in survival, and Paaslik et al.28 define the presence of micrometastases as an independent prognostic factor.

Few studies have been published on micrometastases within the context of gastric cancer, and there has been particularly even less documentation on EGC; within the literature, there is disagreement among authors on the real definition of micrometastases. In a recent report, Siewert et al.5 differentiated microinvolvement, that is neoplastic cells within lymph nodes without surrounding stromal reaction, and micrometastases, defined as clusters of cells with stromal aggregates < 2 mm in size.

In our study, we considered micrometastases as lesions identifiable only by immunohistochemical techniques, as described by Maehara et al. and Iscida et al.1,6 and we used a human anticytokeratin antibody regarded by Ishida as the most sensitive marker.

Most of the lesions observed by us were single cells. Immunohistochemical assay did not reveal aggregates with stromal reaction which had not already been identified using H&E staining.

In our experience, the number of lymph node micrometastases in patients with N0 gastric cancer was very different to that reported by Siewert et al.5 and defined as microinvolvement. In a retrospective immunohistological analysis of 100 patients with pT1–3 N0 and pT1–3 N1 gastric adenocarcinoma, 35 were EGC pN0. Immunohistochemical staining demonstrated the presence of microinvolvement in 14.6% of 1025 lymph nodes dissected. In our study, lymph node micrometastases were present in only 1.7% of 1488 lymph nodes.

In 1995, Maehara et al.14 examined, using immunohistochemical techniques, the dissected lymph nodes of 18 patients with EGC pN0 who died from the recurrence of gastric cancer; he found micrometastases in 22% of those patients. Kashimura et al.29 demonstrated lymph node micrometastases in 23.4% of patients with submucosal EGC pN0.

In our study, we observed lymph node micrometastases in 24 patients (17.3%). Two of the patients who died from gastric cancer recurrence had lymph node micrometastases (10.5%). Of the 71 patients with submucosal EGC, we found micrometastases in 16 (22.5%); this result is similar to that reported by Kashimura et al.29

There are few studies on lymph node micrometastases in patients with EGC and the prognosis for survival. In 1998, Stachura et al.30 did not find any effect on patients’ survival. However, Cay et al.31 demonstrated that fewer patients had a 5-year survival if they had submucosal EGC and lymph node micrometastases (83% vs. 100%). In patients with advanced gastric cancer, Ishida et al.13 reported a statistically significant relation between micrometastases and disease-free interval only for stage II patients, but also commented that the low number of cases examined might have influenced the result. The same author did not observe a statistically significant relation between number of involved lymph nodes and survival, but he reported that the number of micrometastases increases with degree of infiltration as well as in the diffuse histotype.13

Conversely, Siewert et al.5 did report a significance in prognosis for N0 patients only for microinvolvement by three or more tumor cells in more than 10% of the removed lymph nodes. None of our patients fell into this category and did not present statistical significance in prognosis at 5 and 10 years.

It is reasonable to suggest that there is a reduced lymph node microdiffusion in EGC but also that the single cells identified within the lymph nodes may be destroyed by the host’s immune system.

Received for publication May 11, 2000. Accepted for publication September 21, 2000.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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