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Annals of Surgical Oncology 8:605-610 (2001)
© 2001 Society of Surgical Oncology

ORIGINAL ARTICLES

Analysis of Early (pT1) Gastric Cancer With Submucosal Invasion: Surgical Management and Possibility to Schedule Less Invasive Surgery

Shinsuke Takeno, MD, PhD, Tsuyoshi Noguchi, MD, PhD, Ryuichi Kikuchi, MD, PhD, Tetsuro Sato, MD, Yuzo Uchida, MD, PhD and Shigeo Yokoyama, MD, PhD

From the Departments of Surgery II (ST, TN, RK, TS, YU) and Pathology I (SY), Oita Medical University, Oita, Japan.

Correspondence: Address correspondence and reprint requests to: Shinsuke Takeno, MD, PhD, Department of Surgery II, Oita Medical University, 1-1 Idaigaoka, Hasama-machi, Oita, Japan 879-5593; Fax: 81-97-549-4449; E-mail: surg2{at}oita-med.ac.jp


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Early gastric cancer (EGC) is one of the popular targets of less invasive surgery. The aim of the present study is to clarify the possibility of scheduling a less invasive surgery for EGC cases with submucosal (SM) invasion.

Methods: Eighty cases of EGC with SM invasion were analyzed clinicopathologically and immunohistochemically. Correlations between factors that reflect cancer progression and data from endoscopic examination were investigated.

Results: Thirteen cases (16.3%) showed lymph node metastasis and the numbers of metastasis-positive lymph nodes ranged from 1 to 18. Two cases showed lymph node metastasis not only in the perigastric area, but also along the left gastric artery and the common hepatic artery. Only the tumor size showed a significant correlation with lymph node metastasis (P = .014) using the data from preoperative endoscopic examination. With respect to p53 overexpression, there was no significant correlation with pathologic factors in EGC with SM invasion. The simple protuberance types that were <2 cm in diameter had no lymph node metastasis.

Conclusions: It seems difficult to predict the progression of EGC with SM invasion from the data currently obtained by preoperative endoscopic examination. It was suggested that less invasive surgery could be scheduled only for simple protuberance type cases that were <2 cm in diameter. Radical gastrectomy and D2 lymph node dissection is required, in open surgery or laparoscopic surgery, for any other type of EGC with SM invasion.

Key Words: Early gastric cancer with submucosal invasion • Endoscopic examination • p53 • Less invasive surgery • Lymph node metastasis


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Diagnostic and therapeutic techniques involving gastric endoscopy are advancing rapidly. This technique is beneficial for endoscopic mucosal resection (EMR) and for some types of early gastric cancer (EGC) cases. Likewise, laparoscopic surgery has also become more popular, not only for mucosal gastric cancers but also for more progressive gastric cancer. The reduction of surgical invasion can benefit the patients with EGC.1 However, the indication is that the endoscopic or laparoscopic therapy should only be performed in cases with no lymph node metastasis.2,3 Therefore, preoperative evaluation is very important for less invasive surgery.

In addition to radiological data obtained by ultrasonography or computed tomographic scan, we can obtain preoperative data from endoscopic examinations. Endoscopic diagnosis of EGC invasion depth is advancing rapidly. Using endoscopic ultrasonography (EUS), it has been reported that diagnostic accuracy is currently approximately 70%–100% for T1 gastric cancer.4–8 Furthermore, Matsumoto et al.9 report in detail the diagnosis of submucosal invasion using EUS. In contrast, the accuracy of detection of lymph node metastasis is affected by histologic type and is not so exact.4 Thus, it is very difficult to diagnose EGC progression correctly by preoperative EUS. The lymph node metastasis rate is reported to be 11.2% to 23.4% in EGC with submucosal (SM) invasion and the application of less invasive surgery is discussed recently.2,3,10–13 Takeshita2 suggested that a detailed SM subclassification into sm1, sm2, and sm3 was helpful to predict lymph vessel invasion and lymph node metastasis in EGC with SM invasion. However, SM subclassification of cancer invasion with EUS is also very difficult. Therefore, we discussed the possibility of predicting cancer progression from other preoperative endoscopic data in the present study.

Concerning tumor size, a correlation with the progression of EGC is suggested. Histologic features and overexpression of some oncogenes can be shown by microscopic and immunohistochemical examination of biopsy specimens. With respect to overexpression of oncogenes, p53 protein, one of the most important tumor suppressor genes, is reported to be relevant to lymph node metastasis and the pattern of infiltration in gastric cancer.14,15

In the present study, EGC with SM invasion is analyzed clinicopathologically and immunohistochemically, and the possibility of scheduling less invasive surgery and the standard surgical procedure are also discussed.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Eighty patients with EGC and SM invasion (54 males, 26 females) ranging in age from 27 to 86 years (mean, 63.04) were admitted into the present study. These patients had surgical treatment, including gastric resection and extended lymph node dissection, at the Department of Surgery II, Oita Medical University, from January 1989 to December 1998. The extended lymph node dissection was performed in the same manner as D2 in the Japanese system by the Japanese Research Society for Gastric Cancer.16 All cases underwent a curative operation with negative microscopic margins (R0), and they were diagnosed and classified using the TNM classification system by UICC and the Japanese system.16,17

Immunohistochemistry
All resected specimens were fixed in 10% formalin for 24 hours and embedded in paraffin. Sections (4 µm) were placed on silane-coated slides. After deparaffinization and rehydration, sections were placed in 3% hydrogen peroxide for 20 minutes to inactivate endogenous peroxidase, they were then autoclaved at 121°C in citrate buffer (10 mM, pH 6.0) for 10 minutes for antigen activation. After cooling at room temperature for 30 minutes, the specimens were nonspecifically blocked by incubation with normal rabbit serum for 15 minutes at room temperature. Sections were then incubated with anti-p53 monoclonal antibody (DO-7; 1:50; Dako, Carpinteria, CA) for 16 hr at 4°C. Immunohistochemical staining was performed using a standard avidin-biotin-peroxidase, a complex technique using the Histofine SAB-PO kit (Nichirei, Tokyo, Japan). 3,3'-diaminobenzidine was used as the chromogen. Counterstaining of nuclei was performed using hematoxylin. p53 protein overexpression was evaluated in the superficial area of the resected specimen. The depth of superficial area which can be obtained as a biopsy specimen was regarded as 2 mm from the surface of the specimen. Two independent observers evaluated immunohistochemical staining. Immunostaining for p53 protein was measured by the percentage of cancer cells with stained nuclei in more than 500 cancer cells in the same area: 0%–10% (-) and more than 10% (+).

Correlation Analysis Between Cancer Progression and the Data From Endoscopic Examination
The correlation between the data obtained from the endoscopic examination and the pathologic factors of cancer progression was analyzed statistically. The data gained from endoscopic examination were tumor size, configuration, histologic features, and p53 overexpression. For macroscopic configuration, the present series was classified into two groups: simple protuberance type (without depression or ulceration) and depression type (with depression or ulceration). Histologic feature and p53 overexpression can be examined in the biopsy specimen. From the histologic features, differentiated types include papillary and tubular adenocarcinoma. Undifferentiated types were defined as poorly differentiated adenocarcinoma and signet ring cell carcinoma. The pathologic factors which reveal cancer progression are the pattern of infiltration, lymph node metastasis, and lymph- or blood-vessel invasion.

Statistical Methods
For the evaluation of correlations between factors, {chi}2 test or Fisher’s exact probability test was employed. A level of P < .05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Histopathological Classification
In the 80-case series in this study, 57 cases (71.3%) were histologically of the differentiated type and the remaining 23 cases were of the undifferentiated type.

Sixteen cases (20%) showed an expanding growth pattern with clear margins. Thirteen cases (16.3%) involved lymph node metastasis, 24 cases (30%) had lymphatic invasion, and 3 cases (3.8%) had blood vessel invasion. Eleven of the 13 lymph node metastasis-positive cases (84.6%) were accompanied by lymphatic invasion. Conversely, 11 cases had lymph node metastasis among the 24 lymphatic invasion positive cases (45.8%).

Lymph Node Metastasis Pattern
In 13 lymph node metastasis-positive cases, the numbers of metastasis-positive lymph nodes ranged from 1 to 18 (mean, 4.54). Ten of these cases had fewer than six metastasis-positive lymph nodes and were classified as pN1 and stage Ib by UICC classification. Two of the cases each had 7 and 10 metastasis-positive lymph nodes and were classified as pN2 and stage II. The last case had 18 metastasis-positive lymph nodes and was classified as pN3 and stage IV. Eleven cases showed metastasis only in the perigastric area that was classified as pN1 and stage Ib using the Japanese system. One showed lymph node metastasis along the left gastric artery area and was classified as pN2 and stage II, while another case showed metastasis along the common hepatic artery area and was also classified as pN2.

Macroscopic Data From Endoscopic Examination
Tumor diameters did not show the remarkable difference between the preoperative endoscopic examination and the macroscopic observation of resected fresh materials. Thirty-seven cases (46.3%) revealed tumors of <2 cm diameter. Macroscopic configuration showed that 56 cases (70%) were accompanied by depressive features with ulcer formation, and a simple protuberance pattern was seen in 24 cases.

p53 Immunohistochemical Examination
p53 protein overexpression was observed in the nuclei by immunohistochemical staining. Thirty cases (37.5%) reacted positively for anti-p53 monoclonal antibody.

Correlation Analysis Between Cancer Progression and the Data From Endoscopic Examination
Macroscopic configuration and histologic feature showed a significant correlation with data from endoscopic examination (P = .0062)(Table 1). There was a tendency for simple protuberance cancer to reveal a differentiated type. Patient data, gender, and age did not relate to cancer progression of EGC with SM invasion. The only significant correlation was revealed statistically between tumor diameter and lymph node metastasis (P = .014). This suggests that tumors >2 cm in diameter have a higher risk of lymph node metastasis. Only two cases in which tumor diameter was <2 cm had lymph node metastasis. However, the histological type and p53 immunostaining did not show a significant correlation with pathologic factors of cancer progression (Table 2).


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  		TABLE 1. Correlation between factors
 

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  		TABLE 2. Correlation between the data from endoscopic examination and progression factors of early gastric cancer with submucosal invasion
 
The 80 cases in the present study were classified into differentiated and undifferentiated types, and each type was analyzed in the same manner. However, the correlation between tumor size and lymph node metastasis was seen only in the differentiated type (P = .029, data not shown).

Furthermore, the cases which were <2 cm in diameter and of the simple protuberance type were investigated in detail because it has been reported in the literature that these EGC cases have no lymph node metastasis.11 Also, no cases with lymph node metastasis were found in our eight cases (Table 3).


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  		TABLE 3. Cases that were less than 2 cm diameter and simple protuberance type
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Less invasive surgery, represented by laparoscopic local resection without lymphadenectomy, became more popular because the indications for EMR are limited in some EGC. Therefore, the increase in indication for laparoscopic surgery has been discussed recently.13 However, the risk of lymph node metastasis increases remarkably (11.2%–23.4%) compared with mucosal EGC, and it has not been clarified or standardized for the management of EGC with SM invasion.

As described above, 13 cases had lymph node metastasis in the present study. Therefore, uniform use of less invasive surgical technique is not sufficient for curative surgery of EGC with SM invasion, and it is very important to clarify the possibility of less invasive surgery.

There are several reports of EGC with SM invasion concerning the correlation between tumor size and lymph node metastasis.2,11 They suggest that no lymph node metastasis is observed in <2 cm diameter tumors of EGC cases without a depression feature.11 This series, especially in the differentiated type, showed the same correlation in <2 cm diameter cases. However, tumor size showed no correlation with other factors concerning cancer progression. Interestingly, taking macroscopic configuration into consideration, all eight cases that were <2 cm diameter in tumor size and of the simple protuberance type showed no lymph node metastasis. This result is in agreement with previous reports. In these cases, local resection without lymphadenectomy can be curative surgery. However, only one of these cases showed lymphatic vessel invasion and could not be detected with any preoperative endoscopic data. In the literature, lymphatic vessel invasion is indicative of future lymph node recurrent risk.18 Taking the risk of lymph node recurrence into consideration, more caution should be exercised in this case.

A few authors have suggested that histologic type is one of the most important factors indicating less invasive surgery for EGC. Although Sano19 reported that the differentiated type had a higher recurrent risk than the undifferentiated type, no correlation showed for cancer progression in EGC with SM invasion.

p53 is one of the most important tumor suppressor genes and has been reported as a prognostic factor for gastric cancer.14,20–24 Ichiyoshi14 suggests a correlation among p53 overexpression, pathologic factors of cancer progression, lymph node metastasis, and lymph and blood vessel invasion in advanced gastric cancer. Furthermore, Oiwa15 reported a correlation in EGC also between growth pattern and p53 overexpression. However, p53 overexpression revealed no significant correlation with progression factors in EGC with SM invasion. It is reported that the heterogeneity of p53 overexpression is indicative of a mutation in a late event, such as cancer progression, rather than mutation in an early phase, such as carcinogenesis.25 Therefore, in EGC with SM invasion, p53 overexpression might reflect a mutation, not in the cancer progression phase, but in the carcinogenetic early phase because heterogeneity was not remarkable in this series. Recently, there have been several articles describing the correlation between another oncogene and cancer progression factors.26,27 Further study using another oncogene is required in order to clarify the possibility of detecting those cases.

By contrast, the lymph node metastasis pattern of EGC with SM invasion produced interesting results. Almost all cases had lymph node metastasis classified as pN1 by both Japanese and UICC classification. However, two cases had increased lymph node metastasis. It is of particular interest that one case showed 18 metastasis-positive lymph nodes and was classified as stage IV by UICC system. According to the Japanese system, two cases had further metastasis-positive lymph nodes in the area and were classified as pN2. In the literature, Nakamura12 reported that gastrectomy with D1 or D2 lymphadenectomy was required for EGC cases such as these. By contrast, Baba28 recommended gastrectomy with D2 lymphadenectomy for stage I gastric cancer. In the present study, we could not predict these progressive cases from preoperative endoscopic examination. Therefore, these results would also suggest gastrectomy with D2 lymphadenectomy for EGC with SM invasion, except for cases that show <2 cm diameter and simple protuberance.

Extended lymphadenectomy for gastric cancer was suggested to increase morbidity and mortality, compared with D1 lymphadenectomy.29,30 However, laparoscopic gastrectomy with D2 lymph node dissection has been reported recently.31,32 It seems possible to reduce the surgical invasion by using laparoscopic procedures.

Apart from cases with severe complications, we conclude that gastrectomy with D2 lymphadenectomy, in open surgery or laparoscopic surgery, is also required for EGC with SM invasion. For only simple protuberance cases that revealed <2 cm, local resection without lymphadenectomy can be performed. However, when lymphatic vessel invasion is observed pathologically after local resection without lymphadenectomy, strict follow-up with a short interval or a second surgery with D2 lymphadenectomy should be required because of the high risk of lymph node recurrence (Fig. 1).



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  		FIG. 1. How to schedule the surgical treatment for early (pT1) gastric cancer with submucosal invasion.

 
Received for publication September 18, 2000. Accepted for publication April 4, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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