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Annals of Surgical Oncology 9:562-567 (2002)
© 2002 Society of Surgical Oncology

ORIGINAL ARTICLES

Prognostic Impact of Lymphatic and/or Blood Vessel Invasion in Patients With Node-Negative Advanced Gastric Cancer

Woo Jin Hyung, MD, Jun Ho Lee, MD, Seung Ho Choi, MD, Jin Sik Min, MD and Sung Hoon Noh, MD

From the Department of Surgery (WJH, JHL, SHC, JSM, SHN), the Cancer Metastasis Research Center (WHJ, JHL, SHN), and Brain Korea 21 Project for Medical Science (JHL, SHN), Yonsei University College of Medicine, Seoul, Korea.

Correspondence: Address correspondence and reprint requests to: Sung Hoon Noh, MD, Department of Surgery, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-ku, Seoul, Korea; Fax: 82-2-313-8289; E-mail: sunghoonn{at}yumc.yonsei.ac.kr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Heterogeneous survival rates in patients with similar clinicopathologic characteristics or molecular prognostic markers have been noted. This study was conducted to evaluate the prognostic effect of lymphatic and/or blood vessel invasion (LBVI), identified by routine hematoxylin and eosin staining, on the outcome of patients with node-negative advanced gastric cancer.

Methods: A total of 280 patients who underwent curative gastrectomy for advanced gastric cancer without lymph node metastasis were retrospectively reviewed. Univariate and multivariate analyses of the clinicopathological features, recurrences, and prognoses of patients with and without LBVI were performed.

Results: Lymphatic vessel invasion (LVI) was noted in 20.0%, blood vessel invasion (BVI) in 5.4%, and either LVI or BVI in 22.5%. None of the clinicopathologic features was related to LBVI. Patients with LBVI had a recurrence rate of 26.8%, whereas patients without LBVI had a recurrence rate of 13.5% (P = .018). The 5-year survival rates were 82.4% for patients without LBVI and 67.1% for patients with LBVI (P = .0222). LBVI was shown to be an independent risk factor for recurrence (relative risk, 2.30; 95% confidence interval, 1.06–4.99) and poor prognosis (relative risk, 1.88; 95% confidence interval, 1.07–3.29).

Conclusions: LBVI is an adverse prognostic indicator and the presence of LBVI seems to provide useful information for the prognosis and clinical management of patients with node-negative advanced gastric carcinoma.

Key Words: Gastric cancer • Prognosis • Lymphatic invasion • Blood vessel invasion


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although the therapeutic outcomes of patients with gastric adenocarcinoma continue to improve, frequent recurrence remains the main problem after surgical treatment.1,2 The influence of clinicopathologic factors and molecular prognostic markers on recurrence and survival after curative resection has been the subject of many studies, and a variety of clinicopathologic features have been suggested as prognostic indicators for gastric cancers.3–5 However, heterogeneous survival rates in patients with similar clinicopathologic characteristics or similar molecular prognostic markers have been noted.3,4 The validity of molecular markers for prognosis remains controversial among researchers, and their applications are time consuming, complicated, costly, and not widely available.

For patients with gastric adenocarcinoma, depth of invasion and lymph node metastasis have consistently been shown to be independent risk factors for recurrence and prognosis.6,7 Although patients with node-negative gastric cancer have a significantly better prognosis than patients with nodal metastases, a subset of patients with node-negative gastric cancer die of recurrent disease. Therefore, the identification of additional markers that are time and cost efficient and widely available would help in detecting of patients at risk for recurrence among those with node-negative gastric cancer.

Lymphatic and/or blood vessel invasion (LBVI) has been suggested to be a significant prognostic indicator for various types of cancer,8–11 including gastric cancer.12–14 Moreover, several articles have implied the prognostic value of LBVI on clinicopathologic characteristics, including prognosis; however, the results are not consistent, and no study has focused on node-negative advanced gastric cancer. The advanced cancers are defined as tumors that have invaded beyond the submucosal layer, i.e., T2, T3, and T4 by the International Union Against Cancer tumor-node-metastasis classification. This study was conducted to evaluate the prognostic effect of LBVI as determined by routine hematoxylin and eosin (H&E) staining on the outcomes of patients with node-negative advanced gastric cancer.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A retrospective review of prospectively collected gastric cancer data at the Department of Surgery, Yonsei University College of Medicine, from July 1993 to December 1996 revealed 317 patients who had undergone gastrectomies for advanced gastric adenocarcinoma without lymph node metastasis. Six patients who had a history of other-organ cancer before or at the time of operation and five patients with gastric remnant cancer were excluded from this study. Another 17 patients with fewer than 15 lymph nodes retrieved or who underwent D1 lymph node dissection were also excluded because their nodal status might not have been evaluated adequately. A further nine patients were excluded because of incomplete clinicopathologic data or histological slide status, especially LBVI status. As a result, 280 patients with advanced gastric cancer without lymph node metastasis who had undergone curative gastrectomy (R0 resection according to the International Union Against Cancer15) were analyzed according to the presence of LBVI.

The following standardized operative procedures were performed on patients included in the study: (1) total or distal subtotal gastrectomy, depending on the location of the gastric cancer; and (2) D2 or more extended lymphadenectomy. Lymphadenectomy was defined according to the rules of the Japanese Research Society for Gastric Cancer.16

Dissected lymph nodes were retrieved from the excised specimens and recorded by surgeons, and all retrieved lymph nodes were H&E stained and examined for metastasis by light microscopy. Two pathologists reviewed and confirmed all of the pathologic findings. Histological slides and resected specimens were reviewed to confirm the diagnosis, and the following pathologic features were studied: location, macroscopic type, primary tumor size, depth of invasion (shown as serosal invasion), and the number of retrieved lymph nodes. Other variables analyzed included age and sex. As for the histological classification, well or moderately differentiated adenocarcinoma and papillary adenocarcinoma were classified as differentiated type, whereas poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet ring–cell carcinoma were classified as undifferentiated type.

LVI was defined as the presence of neoplastic cell emboli within spaces surrounded by a clearly visualized endothelial lining. We identified BVI by the presence of additional fibrin clots, erythrocytes, or both in an endothelial-lined space without erythrocyte extravasation into the surrounding tissue or by evidence of neoplastic cells within a smooth muscle cell–lined space. A tumor was classified as either LVI negative or BVI negative if the examination of the entire periphery of the tumor on slides revealed no tumor cells within endothelium-lined spaces.

Statistical analyses were performed with SPSS version 10.0 for Windows (SPSS Inc., Chicago, IL). Correlation analysis was performed with the Spearman correlation coefficient. The intergroup comparisons of clinicopathologic variables were performed with Student’s t-test for continuous variables and the {chi}2 test for discrete variables.

Follow-up of patients was conducted until death or the cutoff date (June 30, 2001). At the time of the last follow-up, 11 patients (3.9%) had been lost to follow-up. The median follow-up interval for 193 patients who were alive at the cutoff date was 74 months (range, 55–103 months). There were two (0.7%) postoperative mortalities (within 30 days). Lost cases and operative mortality cases were treated as censored data for the analysis of survival rates. The Kaplan-Meier method was used for calculating the survival rate, and the difference between the curves was assessed by using the log-rank test.17 Risk factors that influenced recurrence and prognosis were determined by multivariate analysis using logistic regression analysis and Cox’s proportional hazard model,18 respectively. Relative risk in the multivariate analysis was defined as the ratio of the probability that an event (recurrence or death) would occur to the probability that it would not occur. The prognostic power of covariates was expressed by calculation of a relative risk with a 95% confidence interval. The accepted level of significance was P < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Incidence
Among 280 lymph node–negative patients with advanced gastric cancer who had undergone curative gastric resection, lymphatic vessel invasion (LVI) was present in 56 patients (20.0%), and blood vessel invasion (BVI) was present in 15 patients (5.4%). LVI and BVI were present concurrently in 8 patients (2.9%), whereas either LVI or BVI was noted in 63 patients (22.5%). Correlation analysis with the Spearman correlation coefficient showed that LVI and BVI were significantly correlated; i.e., the rate of BVI increased as the rate of LVI increased, and vice versa (correlation coefficient, .159; Table 1).


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  		TABLE 1. TABLE 1. Distribution of lymphatic and blood vessel invasiona
 
Comparison of Clinicopathologic Features
Clinicopathologic features such as the age and sex of patients, tumor size, location, depth of invasion, and histological and macroscopic type were not found to be associated with the presence of LBVI. Additionally, the number of retrieved lymph nodes was not related to the presence of vessel invasion (Table 2).


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  		TABLE 2. TABLE 2. Comparative data on lymphatic and/or blood vessel invasion in node-negative advanced gastric cancer patients
 
Recurrence and Survival
Recurrence rates were found to be significantly correlated with the presence of LBVI (P = .018). Patients with LBVI had a recurrence rate of 26.8%, whereas patients without LBVI had a recurrence rate of 13.5% (Table 2). Among 42 patients with recurrent gastric cancer, the exact site of treatment failure was unknown because of incomplete data or lack of confirmatory diagnosis in 9 patients. Of 33 patients whose disease recurrence was identified by confirmatory diagnosis, the main type of treatment failure in patients without LBVI was peritoneal recurrence, whereas that in patients with LBVI was hematogenous recurrence, although statistical significance was not noted (P = .353; Table 3). Logistic regression analysis for tumor recurrence revealed that LBVI was the only independent risk factor for recurrence (relative risk, 2.30; 95% confidence interval, 1.06–4.99; P = .034; Table 4).


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  		TABLE 3. TABLE 3. Comparison of recurrence rate and recurrence pattern according to lymphatic and/or blood vessel invasion
 

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  		TABLE 4. TABLE 4. Logistical regression analysis of risk factors for recurrence
 
The cumulative survival rate was significantly higher in patients without LBVI than in patients with LBVI (P = .022). The 5-year survival rates were 82.4% for patients without LBVI and 67.1% for those with LBVI (Fig. 1). By multivariate analysis with Cox’s proportional hazard model, LBVI turned out to be an independent prognostic factor (relative risk, 1.88; 95% confidence interval, 1.07–3.29; P = .028), as did depth of invasion (Table 5).



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  		FIG. 1. Survival curves of patients with gastric cancer with or without lymphatic and/or blood vessel invasion (LBVI; P = .0222, log-rank test). The 5-year survival rate of patients with LBVI (67.1%) was significantly lower than that of patients without LBVI (82.4%).

 

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  		TABLE 5. TABLE 5. Cox’s proportional hazard model analysis of prognostic factors
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The main finding of this study was that LBVI identified by H&E staining is an independent risk factor for recurrence and is a poor prognostic indicator in patients with node-negative advanced gastric cancer; it is also independent of factors such as tumor size, location, depth of invasion, and histological and macroscopic types.

The incidence of LBVI in gastric cancer varies from 7.2% to 86%.13,19 In this study, the incidence of LVI in node-negative gastric cancer was 20%, which is comparable to other reports of 24.5% to 26.8%.12,14 It is interesting to note that the incidence of BVI in patients with node-negative gastric cancer in this study was 5.4%, which is much lower than the 10.6% previously reported by Gabbert et al.12 and the 20.8% of Inada et al.20 Variations in the incidence of vascular invasion could be caused by the different staining methods or the different criteria used for vascular invasion, as well as by the number of samples examined. The low incidence of BVI in this study is attributed to the absence of an additional staining method to identify the vascular endothelium or smooth muscle cells in blood vessels. Other studies have used immunohistochemistry with factor VIII antigen, CD31, or CD34 for vascular endothelium or have used specific staining for elastic tissue.12,19,20 In this study, BVI was defined either (1) by the presence of neoplastic cells with fibrin clots, erythrocytes, or both in the endothelial-lined space without erythrocyte extravasation in the surrounding tissues or (2) by the neoplastic cells within the smooth muscle cell–lined space. Although the rates of LVI or BVI would have increased if we had used other special staining methods, such as staining for elastic fiber and immunohistochemical staining for vascular endothelium, this study still showed a significant prognostic effect of LBVI independently of other clinicopathologic variables.

The prognostic effect of vascular invasion in gastric cancers, either of LVI or of BVI, which can be detected by routine pathologic examination with H&E stain, has been previously investigated.12–14 However, all of the previous reports have evaluated the role of LBVI in gastric cancer, regardless of the lymph node status of the gastric cancer patients, and have shown a close correlation between lymph node metastasis and LBVI. Because of this correlation, the pure prognostic effect of LBVI could not be assessed by considering lymph node status. No studies have previously focused on the effect of LBVI in patients with node-negative advanced gastric cancer. Lymphatic vessels and blood vessels are widely interconnected and cannot be regarded as independent routes of spread.21 It is difficult to discriminate between lymphatic vessels and blood vessels by routine pathologic examination with H&E staining. As shown in this study, LVI and BVI are closely related12–14; therefore, it is reasonable to regard LBVI as the same pathologic feature if the pathologic features are evaluated by H&E staining alone, without another special staining method.

Depth of tumor invasion, tumor size, and macroscopic type, as well as molecular markers and micrometastasis, have been previously described as prognostic factors in patients with node-negative advanced gastric cancer.22,23 However, heterogeneous survival rates in patients with similar clinicopathological characteristics have been noted. Additionally, newly suggested prognostic factors for various types of molecular markers and micrometastasis also have shown contradictory results, and methods to identify them are time consuming, expensive, complicated, and not widely available.5 Therefore, prognostic markers for patients with the same clinicopathologic features are needed and must be detectable in a time- and cost-efficient manner with the use of readily available methods. In this respect, LBVI, detected by pathologic examination with H&E staining, gives additional information that allows the assessment of the prognosis of patients with node-negative advanced gastric cancer, without the need for additional costly and complicated methods.

However, further study designed to compare the prognostic effect of the presence of LBVI as identified by H&E and other staining methods, such as immunohistochemical staining, is warranted. Moreover, studies are also needed to verify the relationships between LBVI and molecular markers or micrometastasis to evaluate the role of LBVI as a simple alternative for patients with node-negative advanced gastric carcinoma.

In conclusion, LBVI, identified by routine pathologic examinations with H&E staining, is an adverse prognostic indicator independent of tumor size, location, depth of invasion, and histological and macroscopic types for patients with node-negative advanced gastric cancer. Therefore, a careful search for LBVI may provide useful information for prognosis and clinical management in node-negative advanced gastric carcinoma.


   Acknowledgments
 
The authors thank Zak Lancaster for his editorial comments on the manuscript. Supported by the Korea Science and Engineering Fund through the Cancer Metastasis Research Center at Yonsei University.

Received for publication December 18, 2001. Accepted for publication April 10, 2002.


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TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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