Total Versus Subtotal Gastrectomy for Signet Ring Cell Carcinoma of the Stomach

ORIGINAL ARTICLE Total Versus Subtotal Gastrectomy for Signet Ring Cell Carcinoma of the Stomach Ilker Murat Arer 1, Hakan Yabanoglu 1, Aydincan Akdur 2, Nezih Akkapulu 1 and Murat Kus 1 ABSTRACT Objective: To determine the adequate surgery type for the treatment of signet ring cell of stomach in terms of postoperative complications and survival. Study Design: Comparative analytical study. Place and Duration of Study: Baskent University Adana Teaching and Research Center, Adana, Turkey, between 2006 and 2015. Methodology: A total of 46 patients with the diagnosis of gastric signet ring cell, who underwent total or subtotal gastrectomy, were enrolled in this study. Patients were compared according to age, gender, tumor location, TNM stage, survival and mortality rates, operation time, complication and recurrence. Comparisons between groups were performed by using Mann-Whitney U-test for the data not normally distributed. The categorical data were analyzed by using the Chisquare test or Fisher's exact test, where applicable. Kaplan-Meier test was used for survival curve and Long-rank test was used for survival differences between groups. Values of p < 0.05 were considered statistically for all tests. Results: Of the 46 patients, 29 (63.0%) were male. The mean age was 56.6 ±13.2 years. The median tumor size was 5.0 cm (IQR: 3.0-6.6). Twenty-six (56.5%) patients were in total gastrectomy, whereas 20 (43.5%) were in subtotal gastrectomy group. Five-year cumulative survival rate was 0.487. Five-year overall survival rate for early and advanced signet ring cell carcinoma was 0.830 and 0.164, respectively (p<0.001). Five-year overall survival rate for total and subtotal gastrectomy groups were 0.422 and 0.582, respectively (P=0.417). Complications were observed in 17.4% (n=8) of all 46 patients. Conclusion: Subtotal gastrectomy can be performed safely for patients with gastric signet ring cell carcinoma and is equal to total gastrectomy with respect to prognosis and complication rates. Key Words: Gastric cancer. Signet ring cell. Subtotal gastrectomy. Total gastrectomy. 5-year survival rate. Prognosis. INTRODUCTION Signet ring cell carcinoma (SRC) is an adenocarcinoma composed of isolated or small groups of malignant cells containing intracytoplasmic mucin pool as predominant component (more than 50% of the tumor). 1 SRC can also be classified as diffuse, infiltrative and undifferentiated type by different classifications. 2-4 Although improvement in the survival of patients with gastric cancer has been reported due to early diagnosis, lymphadenectomy and other treatment modalities; SRC is reported to have different histopathological features, characteristics and survival rates. Some authors state that clinical outcomes of SRC differ according to whether it is early or advanced. 5 Early gastric SRC has variously been reported to have favorable or similar outcomes compared with non-src types and advanced SRC. 6-8 1 Department of General Surgery, Baskent University Adana Teaching and Research Centre, Adana, Turkey. 2 Department of General Surgery, Baskent University School of Medicine, Ankara, Turkey. Correspondence: Dr. Ilker Murat Arer, Department of General Surgery, Baskent University Adana Teaching and Research Center, Dadaloglu District 2591, Street No: 4/A 01250 Yuregir, Adana, Turkey. E-mail: igy1981@yahoo.com Received: October 24, 2016; Accepted: October 10, 2017. Surgical resection seems to be the most effective treatment modality for these kind of tumors. However, surgical resection has no benefit on advanced tumors in case of peritoneal carcinomatosis. Type of surgical resection performed for gastric cancer is still controversial. Both total or subtotal gastrectomy are prefered for treatment according to location of the tumor. 9 Although gastric resection type for SRC has not been investigated seperately yet. The aim of the present study was to compare survival rates and recurrence of total and distal gastrectomy for the treatment SRC of the stomach. METHODOLOGY Patients who had diagnosis of gastric SRC, underwent total or subtotal gastrectomy between 2006 and 2015 were enrolled in this study. Seven patients with positive surgical margins were excluded. Thus, 46 patients were divided into two groups according to surgical technique, i.e. total gastrectomy (TG, Group 1) and subtotal gastrectomy (SG, Group 2). Data were collected retrospectively. Patients were compared according to age, sex, tumor location, TNM stage, survival and mortality rates, operation time, complication and recurrence. This study was approved by Baskent University Institutional Review Board (Project No: KA15/200) and supported by Baskent University 616 Journal of the College of Physicians and Surgeons Pakistan 2017, Vol. 27 (10): 616-620

Gastrectomy for signet ring cell carcinoma Research Fund. Informed patient content was not taken due to retrospective design of the study. Statistical analysis was performed using the statistical package SPSS software (Version 17.0, SPSS Inc., Chicago, IL, USA). Normally distributed continuous variables were described as the mean ± standard deviation (p>0.05 in Kolmogorov-Smirnov test or Shapiro-Wilk (n<30). Skewed continuous variables were described as the median (IQR). Comparisons between groups were performed by using Mann-Whitney U-test for the data not normally distributed. The categorical data were analyzed by using the Chi-square test or Fisher's exact test, where applicable. Kaplan-Meier test was used for survival curve and Long-rank test was used for survival differences between groups. Values of p < 0.05 were considered statistically for all tests. RESULTS A total of 46 patients enrolled in this study; 29 (63.0%) were male. The mean age was 56.6 ±13.2 years. The median tumor size was 5.0 (IQR: 3.0-6.6) cm. Of the 46 patients, 26 (56.5%) were in TG group whereas 20 (43.5%) were in SG group. The most common complaint of patients was abdominal pain (32, 69.6%). The tumor was located in the upper third of the stomach in six (13.0%) patients, middle third in five (10.9%) patients, distal third in 21 (45.7%) patients and whole stomach in 14 (30.4%) patients. Characteristics of patients are summarized on Table I. The most common macroscopic appearance of the tumor was ulcer (n=36, 78.3%). Depth of tumor invasion was through mucosa and submucosa in 8 (17.4%) and serosa and subserosa in 38 (82.6%) patients. Perineural and lymphovascular invasion were found in 39 (84.8%) and 40 (87.0%) patients, respectively. There was no significant difference between groups according to TNM stage (p=0.924 for T, p=0.700 for N, P=0.184 for M) and grade of the tumor (p=0.348). The median number of total lymph node extracted was 19.5 (between 0-83) and median number of metastatic lymph node was five (0-82). Median follow-ups of patients were 17.5 months (0-103 months). Twenty-four (52.2%) patients received adjuvant chemotherapy whereas 20 (43.5%) patients had adjuvant radiotherapy. Nine (34.6%) patients in TG group and three (15.0%) patients in SG group had recurrent disease. However, total gastrectomy was performed for 2 patients with recurrent disease in SG. The median durations of operation were 215 and 180 minutes (between 150-300 vs. 60-270) for TG and SG groups, respectively; that is found to be statistically significant (p=0.002). Five-year cumulative survival rate was 0.487. The crude survival proportion was 58.7% (27 of 46 patients survived). Five-year overall survival rates Table I: Characteristics of patients performed total gastrectomy and subtotal gastrectomy with SRC carcinoma. TG, n=26 (%) SG, n=20 (%) P-value Gender 0.708 Male 17 (65.4) 12 (60.0) Female 9 (34.6) 8 (40.0) Age (years)* 55.5 (47.7-63.0) 57.5 (46.5-70.0) 0.715 Tumor size (cm)* 6.0 (4.0-7.2) 5.0 (3.0-6.0) 0.109 Tumor location 0.106 Upper 5 (19.2) 1 (5.0) Middle 4 (15.4) 1 (5.0) Lower 8 (30.8) 13 (65.0) Whole 9 (34.6) 5 (25.0) Macroscopic appearance 0.293 Ulcer 19 (73.1) 17 (85.0) Polyp 3 (11.5) 0 (0.0) Infiltrative 1 (3.8) 2 (10.0) Depth of tumor invasion 0.978 Mucosa 1 (3.8) 1 (5.0) Submucosa 3 (11.5) 3 (15.0) Subserosa 9 (34.6) 7 (35.0) Serosa 13 (50.0) 9 (45.0) Lymphovascular invasion Yes 24 (92.3) 16 (80.0) 0.380 No 2 (7.7) 4 (20.0) Perineural invasion 0.682 Yes 23 (88.5) 16 (80.0) No 3 (11.5) 4 (20.0) Stage Early 9 (34.6) 8 (40.0) 0.708 Advanced 17 (65.4) 12 (60.0) Lymph node number* Metastatic 6 (0-17) 4.5 (0-8) 0.260 Total 26 (17-36) 14 (11-20) 0.002 Chemotherapy 0.254 Adjuvant 12 (46.2) 12 (60.0) Neoadjuvant+Adjuvant 3 (11.5) 0 (0.0) None 11 (42.3) 8 (40.0) Radiotherapy 0.434 Yes 10 (38.5) 10 (50.0) No 16 (61.5) 10 (50.0) Operation time (minutes)* 215 (180-240) 180 (180-180) 0.002 Follow-up (months)* 16 (5-49.5) 19 (4-58) 0.833 Recurrence 9 (34.6) 3 (15.0) 0.133 *Values are median and in parenthesis interquartile ranges. SG = Subtotal gastrectomy; TG = Total gastrectomy. for TG and SG groups (Figure 1a) were 0.422 and 0.582, respectively (p=0.417). The 5-year overall survival rate for early and advanced SRC carcinoma (Figure 1b) was 0.830 (crude survival proportion 82.4%, 14 of 17 patients survived) and 0.164 (crude survival proportion 44.8%, 13 of 29 patients survived), respectively (p<0.001). Fiveyear survival rate for patients with metastatic lymph node (Figure 1c) was 0.354. The crude survival proportion was 46.9% (15 of 32 patients survived). Without metastatic lymph node, it was 0.771 (the crude survival proportion 85.7%, 12 of 14 patients survived); that was found to be statistically significant (p=0.003). However, 5-year survival rate for patients in TG with Journal of the College of Physicians and Surgeons Pakistan 2017, Vol. 27 (10): 616-620 617

Ilker Murat Arer, Hakan Yabanoglu, Aydincan Akdur, Nezih Akkapulu and Murat Kus metastatic lymph node (Figure 1d) was 0.246. The crude survival proportion 42.1%, 11 of 19 patients survived) and 0.577 in SG group (crude survival proportion 53.8%, 7 of 13 patients survived). No statistically significant difference was observed (p=0.479). Figure 1d: Survival of patients with metastatic lymph node according to surgery type. Figure 1a: Overall survival of patients with gastric signet ring cell carcinoma according to surgery type. Figure 1b: Survival of patients with gastric signet ring cell carcinoma according to stage of the tumor. Figure 1c: Survival of patients with gastric signet ring cell carcinoma according to presence of metastatic lymph node. Complications were observed in eight (17.4%) of all 46 patients including intraabdominal abscess (6.5%), surgical site infection (6.5%), deep vein thrombosis (2.2%), and pneumonia (2.2%). Complication rate for TG and SG was 19.2% and 15.0%, respectively (p=0.673). Overall mortality rate was 41.3% (n=19). The common causes of mortality were pulmonary insufficiency, pneumonia and pancytopenia. DISCUSSION SRC of the stomach is responsible for 3.4-29% of all gastric cancers and is common in younger age and women. 10-12 In this current study, incidence of SRC is found to be 14%. This histological type of gastric cancer has been evaluated for characteristics and prognosis by many studies, but no specific surgery type has been identified, yet. 6,13,14 There is no consensus on type of the surgery, both total or subtotal gastrectomy can be performed in gastric cancer. Although radical gastrectomy with lymph node dissection still seems to be the gold-standard treatment of gastric cancer, literature shifts from radical to minimally invasive surgery. Unless gastric SRC is seen in females predominantly, we observed higher male ratio (66%). This finding is different from our literature knowledge. Heger et al. observed similar findings as in this study, male predominancy as 62.1%. 15 This can be explained by environmental factors affecting tumor histology in different geographical areas. Younger age and female predominance of SRC and undifferentiated-type gastric cancers are still unclear but influence of the histology by sex hormones is explained by a theory. 16,17 Kwon et al. found the most common endoscopic appearance of the tumor as depressed (51-70.2%), corresponding to ulcerative appearance in pathology specimen. 14 Kim et al. observed the most common gross appearance as depressed (82.1-86.4%) in surgical specimen of intramucosal spreding pattern of SRC. 18 Finding of the current study correlates with literature 618 Journal of the College of Physicians and Surgeons Pakistan 2017, Vol. 27 (10): 616-620

Gastrectomy for signet ring cell carcinoma data; thus most common appearance of the tumor was ulcer in 78.3% of all pathology specimen. Hyung et al. found the similar results (76.1%) as the present study. 6 Perineural and lymphovascular invasion is commonly seen in gastric SRC. Kwon et al. found perineural and lymphovascular invasion rates to be 7.8-56.1% and 11.8-64.9% respectively, depending on either the tumor is early or advanced. 14 Selcukbiricik et al. observed lower survival rates in patients with lymphovascular and perineural invasion found to be statisically significant. 19 Higher invasion rates in our study (84.8% and 87%), may lead to higher recurrence rates (15-34.6%). Curative resection with adequate surgical margins is the only effective treatment for patients with resectable gastric cancer, and subtotal gastrectomy is accepted as the gold standard therapy for early-stage gastric cancer located in the distal third of the stomach. 9 Total gastrectomy may be performed in patients with poorly differentiated histological type located in the angularis portion of the stomach. 20 Kwon et al. performed subtotal gastrectomy (66%) for early SRC and achieved curative surgery 92.2%, whereas total gastrectomy (64.9%) for advanced SRC and achieved curative surgery 73.7%. 14 Gronnier et al. performed total gastrectomy (58%) for SRC and found this morphologic subtype of gastric cancer not to be a negative prognostic factor in early tumors. 21 Lee et al. investigated patients with tumors in the middle third of the stomach who underwent TG and SG and found survival rates to be 38.1% and 69% respectively (p>0.05) and recommend SG instead of TG if negative surgical margins can be obtained. 22 Total gastrectomy (56.5%) was the most commonly performed procedure in our current study. However, patients in TG group had recurrent disease (34.6%) frequently. Subtotal gastrectomy was reported to be superior to total gastrectomy in terms of preserving functions of the stomach, lower short-term morbidity and mortality rate, shorter hospital stay, higher calorie intake and better nutritional status with improved quality of life in the long follow-up, 9,23,24 as well as less recurrence rate (15%). Recurrent disease was observed in only two patients in SG group who had received total gastrectomy. The authors encourage subtotal gastrectomy for gastric SRC depending on the location of the tumor. The prognosis of patients with SRC in the literature are controversial. Comparing with other histopathological types, prognosis of SRC is found to be better or worse. Jiang et al. found curability of SRC with surgery for advanced cases as 75.2% and better prognosis than other histopathological types; but the cumulative and overall 5-year survival was 31.5% and 49.8%, respectively. 7 Hyung et al. found better survival rates; the 5- and 10-year survival rates were 94.2% and 89.7% for patients with early SRC, respectively. 6 Park et al. reported overall cumulative and disease-free 5-year survival rate for SRC to be 66.2% and 64.5%. 25 Gronnier et al. also found better 5-year overall survival rate (85%). 21 The present findings of 5-year survival rate in early and advanced SRC carcinoma, as the tumor gets advanced or in the presence of metastatic lymph node, demonstrate aggressive growth pattern and yield lower survival rate. However survival rate of total and subtotal gastrectomy groups were not significantly different. Survival rate of subtotal gastrectomy was better even in case of presence of metastatic lymph node. 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