Lymph Node Metastasis in Early Signet Ring Cell Carcinoma: Feasibility of Endoscopic Mucosal Resection

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Author: ping lu, hua li

Lymph Node Metastasis in Early Signet Ring Cell Carcinoma: Feasibility of Endoscopic Mucosal Resection Hua Li1, Ping Lu1*, Jing Zhang2, Huimian Xu1, Shubao Wang1, Junqing Chen1 1Department of Oncology, First Affiliated Hospital of China Medial University, Shenyang 110001, China 2Department of Physiology, Institute of Basic Medicine Hebei Medical University, Shijiazhuang 050017, China Hua Li, Department of Oncology, First Affiliated Hospital of China Medical University, shenyang 110001,China. MobilePhone:13478158258. E-mail: lihua200626478@sohu.com

*Corresponding author Dr. Ping Lu, Department of Oncology, First Affiliated Hospital of China Medial University, Shenyang 110001, Liaoning Province, China. Email: lupingluyang@sohu.com Tel: +86-134 78158258 Fax: +86-24-2283 4060. Supported by the Nature Science Foundation of liao ning (No.20042071)

Abstract Objective:

To identify clinicopathological factors predictive of lymph node metastases (LNM) in early signet ring cell carcinoma (SRC), and further to expand the possibility of using endoscopic mucosal resection (EMR) for the treatment of early SRC. Methods: Data from 27 patients with early SRC and surgically treated were collected, and the association between the clinicopathological factors and the presence of LNM was retrospectively analyzed by univariate and multivariate logistic regression analyses. Results: In the univariate analysis, a tumor larger than 3.0 cm, submucosal invasion, and the presence of lymphatic vessel involvement (LVI) were significantly associated with a higher rate of LNM (all PBackground Endoscopic mucosal resection (EMR) has been widely accepted as an alternative treatment to surgery for early gastric cancer (EGC) [1 - 3]. The application of EMR has been limited to differentiated EGC because of the higher risk of lymph node metastases (LNM) in undifferentiated EGC, compared to differentiated EGC [4 - 6]. Therefore, gastrectomy with lymphadenectomy has been considered to be an essential treatment for patients with undifferentiated EGC. Undifferentiated carcinoma of gastric cancer includes poorly differentiated adenocarcinoma, signet ring cell carcinoma, and mucinous adenocarcinoma [7]. The lower rate of lymph node metastasis and favorable prognosis of early SRC indicate its suitability for less invasive surgery [8, 9]. Therefore, we carried out this retrospectively study to determine the clinicopathological factors that are predictive of LNM in early SRC. Furthermore, we established a simple criterion to expand the possibility of using EMR for the treatment of early SRC. Methods Patients Patients underwent a radical operation due to EGC in the Department of Oncology, First Affiliated Hospital of China Medical University, Shengyang, China, between January 1980 and December 2003 were included in the screening for identification of cases with EGC in this retrospective study. The inclusion criteria for this study were: 1), lymph node dissection beyond limited (D1) dissection; 2), the resected specimens and lymph nodes were pathologically analyzed, and early SRC was diagnosed, according to the Japanese Classification of Gastric Carcinoma (JCGC) [7]; and 3), patient¡¯s medical record were available in the database. During the 24 years, operation was performed in 261 EGC patients, and 28 patients were histologically diagnosed as having early SRC. Among the 28 patients with early SRC, medical record was not completed available for 1 case. Thus, 27 patients (18 male, 9 female; mean age 45 years, range 37-69 years) with histopathologically early SRC type were identified to meet the inclusion criteria for further analysis in this study. The study protocol was approved by the Ethics Committee of China Medical University. Surgically dissection of lymph nodes Lymph nodes were meticulously dissected from the enbloc specimens, and the classification of the dissected lymph nodes was determined by surgeons who reviewed the excised specimens after surgery based on the JCGC [7]. Then, the resected lymph nodes were sectioned and stained with hematoxylin and eosin and examined by pathologists for metastasis and lymphatic vessel involvement (LVI).

Association between clinicopathological parameters and lymph node metastasis Clinicopathological parameters that are covered in the JCGC [7] were included in this study. They were the gender (male and female), age (3 cm), macroscopic type (protruded [type I ], superficial elevated [type IIa], flat [type IIb], superficial depressed [type IIc], or excavated [type III]), depth of invasion (mucosa, submucosa), lymphatic vessel involvement. The associations between various clinicopathological factors and LNM were examined as described below.

Statistical analysis All data were analyzed using SPSS13.0 statistical software (Chicago, IL United States). The differences in the clinicopathological parameters between patients with and without LNM were determined by the ¦Ö2 test. A multivariate stepwise logistic regression analysis was performed subsequently in order to identify independent risk factors for LNM. Hazard ratio and 95% confidence interval (CI) were calculated. A P value of less than 0.05 was considered statistically significant.

Results

Association between clinicopathological parameters and lymph node metastasis The association between various clinicopathological characteristics and LNM was first analyzed by the ¦Ö2 test (Table 1). A tumor larger than 3.0 cm, submucosal invasion, and the presence of LVI were significantly associated with a higher rate of LNM (all PDISCUSSION One of the critical factors in choosing EMR for EGC would be the precise prediction of whether the patient has LNM or not. To achieve this goal, several studies have attempted to identify risk factors predictive of LNM in EGC. Few reports, however, have focused on the applicability of endoscopic treatment for early SRC. The present multivariate analysis revealed that the presence of LVI was significant predictive factor for LNM in patients with early SRC. Our results collaborate those of previous reports on early SRC, which demonstrated a significant correlation between the high incidence of LNM and presence of LVI. In contrast, in comparing the LNM rate between intramucosal lesions and submucosally invasive lesions, a lower LNM rate was found in the former group by univariate analysis (5.6% versus 44.4%), although the association between the LNM rate and depth of invasion showed no statistical significance by multivariate analysis, which is not consistent with previous studies [9¨C11]. Furthermore, no significant association between the LNM rate and tumor size was found. This factor has always been taken as risk factor for LNM for early SRC [9¨C11]. We then attempted to identify a subgroup among early SRC patients in whom the risk of LNM can be highly ruled out, namely candidates who can be curably treated by EMR. As a result, we found no LNM in patients with intramucosal cancer if the tumor is less than or equal to 3.0 cm in size without LVI. This may indicate that EMR could be sufficient to treat these cases, and that additional surgery is unnecessary. The LNM rates were 20%, 40% and 66.7%, respectively, in cases with one, two and three risk factors (a tumor larger than 3.0 cm, submucosal invasion, and the presence of LVI). Therefore gastrectomy with lymphadenectomy is inevitable for these patients with the risk factors. All the information regarding these predictive factors, particularly LVI, becomes first evident after the histological assessment of the entire specimen endoscopically obtained. Thus, an accurate histological examination of the endoscopically resected specimen is required to determine whether EMR alone is curative or not. A new EMR technique, complete removal of a large lesion in a single fragment using an insulation-tipped diathermic knife [12¨C15], is a promising procedure for this purpose. In conclusion, EMR alone may be sufficient treatment for intramucosal early SRC if the tumor is less than or equal to 3.0 cm in size, and when LVI is absent upon postoperative histological examination. When specimens shows with LVI, an additional radical gastrectomy with lymphadenectomy should be recommended.

References

1. Makuuchi H, Kise Y, Shimada H, et al. Endoscopic mucosal resection for early gastric cancer. Sem Surg Oncol 1999;17:108¨C116. 2. Ishikawa S, Togshi A, Inoue M, et al. Indications for EMR/ESD in cases of early gastric cancer: relationship between histological type, depth of wall invasion, and lymph node metastasis. Gastric Cancer 2007; 10:35-38. 3. Gotoda T, Yamamoto H, Soetikno RM. Endoscopic submucosal dissection of early gastric cancer. J Gastroenterol 2006; 41:929¨C942. 4. Hyung WJ, Cheong JH, Kim J, et al. Application of minimally invasive treatment for early gastric cancer. J Surg Oncol 2004;85:181¨C185. 5. Abe N, Watanabe T, Sugiyama M, et al. Endoscopic treatment or surgery for undifferentiated early gastric cancer? Am J Surg 2004; 188:181¨C184. 6. Nasu J, Nishina T, Hirasaki S, et al. Predictive factors of lymph node metastasis in patients with undifferentiated early gastric cancers. J Clin Gastroenterol 2006; 40:412¨C415. 7. Japanese Gastric Cancer Association, Japanese classification of gastric carcinoma. 2nd English ed. Gastric Cancer 1998; 1:10-24. 8. Hyung WJ, Noh SH, Lee JH, et al. Early gastric carcinoma with signet ring cell histology. Cancer 2002; 94:78¨C83. 9. Kunisaki C, Shimada H, Nomura M, et al. Therapeutic strategy for signet ring cell carcinoma of the stomach. Br J Surg 2004; 91:1319¨C1324. 10. Ha TK, An JY, Youn HK, et al. Indication for endoscopic mucosal resection in early signet ring cell gastric cancer. Annals of Surgical Oncology 2007; 15:508-513. 11. Dong Yi Kim, Young Kyu Park, Jae Kyoon Joo, et al. Clinicopathological characteristics of signet ring cell carcinoma of the stomach. ANZ J. Surg 2004;74: 1060¨C1064 12. Gotoda T, Kondo H, Ono H, et al. A new endoscopic mucosal resection procedure using an insulation-tipped electrosurgical knife for rectal lesions: report of two cases. Gastrointest Endosc 1999; 50:560¨C563. 13. Kondo H, Gotoda T, Ono H, et al. Early gastric cancer: endoscopic mucosal resection. Ann Ital Chir 2001; 72:27¨C31. 14. Ohkuwa M, Hosokawa K, Boku N, et al. New endoscopic treatment for intramucosal gastric tumors using an insulation-tip diathermic knife. Endoscopy 2001; 33:221¨C226. 15. Miyamoto S, Muto M, Hamamoto Y, et al. A new technique for endoscopic mucosal resection with an insulation-tip electrosurgical knife improves the completeness of resection of intramucosal gastric neoplasms. Gastrointest Endosc 2002; 55:576¨C581.

Table 1 Univariate analysis of potential risk characteristics for lymph node metastasis

Lymph node metastasis Factor Positive number (%) P Value Sex Male (n=18) 4 (22.2%) 0.484 Female (n=9) 1 (11.1%) Age£¨years£© 3 cm (n=10) 4( 40.0%) Macroscopic type I (n=0) 0(0%) 0.171 II (n=22) 3(13.6%) III (n=5) 2(40.0%) Depth of invasion Mucosa (n=18) 1(5.6%) 0.014 Submucosa (n=9) 4(44.4%) Lymphatic vessel involvement Negative (n=24) 3(12.5%) 0.023 Positive (n=3) 2(66.7%)

Table 2 Multivariate analysis of potential risk factors for lymph node metastasis

Characteris Hazard ratio 95% confidence interval P Value Tumor size 15.240 0.500£­464.965 0.118 ¡Ü 3 cm >3cm Depth of invasion 0.281 0.009£­8.587 0.467 Mucosa Submucosa Lymphatic vessel involvement 32.054 1.419£­751.322 0.029 Negative Positive

Table 3 Relationship between the number of risk factors (a tumor larger than 3.0 cm, submucosal invasion, and the presence of LVI) and lymph node metastasis in early SRC Number of positive risk factors Nodal metastasis rate (%) None 0%(0/14) One 20%(1/5) Two 40%(2/5) Three 66.7%(2/3)