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Clinicopathological features and outcomes in patients undergoing radical resection for early gastric cancer with signet ring cell histology
Journal of Visceral Surgery (2015) 152, 357—361
Available online at
ScienceDirect www.sciencedirect.com
ORIGINAL ARTICLE
Clinicopathological features and outcomes in patients undergoing radical resection for early gastric cancer with signet ring cell histology Z. Wang , X. Zhang , J. Hu , W. Zeng , Z. Zhou ∗ Cancer Hospital of the Chinese Academy of Medical Sciences, Peking Union Medical College, the Department of Abdominal Surgical Oncology, Beijing, China Available online 23 October 2015
KEYWORDS Early gastric cancer; Signet ring cell histology; Prognosis
Summary Background: The signet ring cell histology is regarded as an independent predictor of poor prognosis in advanced gastric adenocarcinomas, but its biologic behavior in early gastric cancer remains highly controversial. Objective: Our objective was to compare the clinicopathological features and outcomes in patients undergoing curative resection between SRCs and non-SRCs histologic types of early gastric cancer. Methods: Clinicopathologic features and the overall survival rates of 334 patients with early gastric cancer undergoing D2 curative resection from January 1994 to December 2008 were retrospectively reviewed and compared according to the histologic type. Results: Clinicopathologic features were comparable between two groups, except age, ulcer findings and the presence of lymph node metastasis. The incidence of recurrence for SRCs group was significantly lower than that for non-SRCs group (10.4% vs 19.6%; P < 0.05). The overall 5-year survival rate was 88.6% in all cases. The overall survival rate of patients in SRCs group was significantly better than that of patients in non-SRCs group (5-year survival, 93.9% vs 85.8%; P = 0.027). Multivariable analysis revealed that SRCs subtype, lymphovascular invasion, and lymph node metastasis were independent prognostic factors. Conclusion: Our analysis revealed that the biological behavior of SRCs was different from other undifferentiated cancer histologic subtypes in early stage. Early gastric cancer with signet ring cell histology had low incidence of lymph node metastasis and a relatively favorable prognosis. © 2015 Elsevier Masson SAS. All rights reserved.
Introduction ∗
Corresponding author. E-mail address: [email protected] (Z. Zhou).
http://dx.doi.org/10.1016/j.jviscsurg.2015.09.021 1878-7886/© 2015 Elsevier Masson SAS. All rights reserved.
In 1962, the Japanese Society of Gastroenterological Endoscopy defined early gastric cancer as a lesion confined
358 to the mucosa and/or submucosa, regardless of lymph node metastatic status [1]. The need to define this category of gastric cancer is related to the difference in prognosis between early and advanced gastric cancer. The prognosis is generally favorable in early gastric cancers after radical surgery, with a 5-year survival rate of more than 90% [2,3]. The proportion of early gastric cancer among all gastric cancers has increased to nearly 50% in Japan and Korea [4—6]. With more widespread mass screenings, as well as advances in endoscopic techniques and equipment, similar trends have been observed during the past few decades in China. According to the Japanese Gastric Cancer Association, undifferentiated gastric carcinoma includes poorly differentiated adenocarcinoma, mucinous adenocarcinoma and signet ring cell carcinoma [7]. Signet ring cell carcinomas (SRCs) are defined as gastric cancers in which the predominant component consists of isolated or small groups of malignant cells containing intracytoplasmic mucins [8]. Generally, SRCs and poorly differentiated adenocarcinomas, mucinous adenocarcinoma are associated with an ominous outcome. However, the prognostic significance of SRCs histologic subtype in early stage remains controversial. Some studies have reported that SRCs have a lower incidence of lymph node metastasis and favorable prognosis than other undifferentiated cancer histologic subtypes [9,10]. For this reason, undifferentiated early gastric carcinoma includes SRCs subtype and non-SRCs subtype should be investigated separately with regard to oncologic outcomes. The aim of this retrospective study was to compare the clinicopathologic features and outcomes between SRCs group and non-SRCs group in patients undergoing radical resection for early gastric cancer.
Patients and methods Patients Institutional review board approval was obtained before conducting this study. A total of 334 patients who had undergone radical (R0) gastrectomy with D2 lymph node dissection for histologically proven undifferentiated early gastric cancer from January 1994 to December 2008 at the Department of Abdominal Surgical Oncology, Cancer Hospital of the Chinese Academy of Medical Sciences, Peking Union Medical College were selected for this study. Cases with recurrence or multifocal gastric cancer were excluded. Histology was classified according to the Japanese Gastric Cancer Association [7]. All the patients routinely underwent an upper alimentary tract barium meal and electronic gastroscope examination before surgery to identify the diseased region and the pathologic type to confirm the diagnosis of malignant neoplasm of the stomach after pathologic examination. The preoperative routine chest X-ray, abdominal ultrasound, and upper abdominal CT examination showed no pulmonary, hepatic, or other distant metastases and no tumor directly invading the pancreas, spleen, liver, or colon. Endoscopic ultrasound examination was not performed routinely. All patients underwent radical subtotal or total gastrectomies, depending on the tumor location and intraoperative verification of tumor-free resection margins, as well as D2 lymphadenectomies. Those with tumors located in the lower third of the stomach underwent distal gastrectomy. Patients with tumors in the middle third of the stomach underwent either distal
Z. Wang et al. gastrectomy or total gastrectomy according to the direction of the tumor invasion. Proximal gastrectomy was used for patients with tumors in the upper third of the stomach, and total gastrectomy was used for those with tumors occupying the entire stomach. In this series, distal gastrectomy was performed in 283 patients, total gastrectomy was performed in 33 patients, and proximal gastrectomy was performed in 18 patients. No patient has received neoadjuvant therapy before surgery. The methods of reconstruction after distal gastrectomy include Billroth I, II or Roux-enY. Roux-en-Y reconstruction and jejunal interposition are the most common methods used after a total gastrectomy. All specimens were examined after resection. World Health Organization criteria for histological typing of gastric tumors were used, where signet ring cell carcinoma is defined as an adenocarcinoma in which a predominant component (more than 50% of the tumor) is made up of isolated or small groups of malignant cells containing intracytoplasmic mucin. The formalin-fixed specimens were cut into multiple slices, principally parallel to the lesser curvature, at an interval of 3 mm. The hematoxylin and eosin stained sections of tumor were examined. A single pathologist retrieved all lymph nodes by palpation under gross inspection. The lymph nodes were cut into two pieces along the long axis, embedded in paraffin blocks, and stained with haematoxylin and eosin. Of these patients, SRCs group had 115 patients (34.4%), and non-SRCs had 219 patients (65.6%). The patients’ clinical characteristics, histopathological parameters and followup data were analyzed. Clinicopathological factors, such as sex-ratio, age, tumor size, tumor location, macroscopic appearance, histological type, ulceration, depth of tumor invasion, lymph node status and lymphovascular invasion were defined according to the Japanese Classification of Gastric Carcinoma [7]. The maximum diameter of tumor was recorded as tumor size. Macroscopic type includes elevated (I, protruded; IIa, superficial elevated), flat (IIb, superficial flat), and depressed (IIc, superficial depressed; III, excavated). Lesions with ulceration or scarring from previous ulceration (converging folds or deformity of the muscularis propria, or fibrosis in the submucosal or deeper layer) within them were regarded as ulcerated lesions. The depth of tumor invasion was classified as mucosa and submucosa carcinoma. Lymphovascular invasion was defined as the presence of tumor emboli either in the lymphatic duct or the vascular lumen. Overall survival and the pattern of recurrence were compared between the two groups. Patients with SRCs were considered as the reference group for statistical analysis.
Follow-up All patients who survived the operation were followed until death or the cutoff date (March 31, 2014). All patients were followed up regularly at 3-month intervals in the first 2 years and the every 6 months thereafter for clinical examination including chest X-ray, abdominal and pelvic ultrasound or CT and tumor markers. Follow-up evaluation was implemented by means of outpatient service, telephone calls, and letters. Median follow-up period were 97 months (range, 66—236). Only deaths due to early gastric cancer were considered. Deaths due to other causes were censored at the date of death. Three patients were lost to follow-up. These patients were excluded from the present study.
Early gastric cancer with signet ring cell histology Table 1
359
Comparison of clinicopathologic features between patients with SRCs and non-SRCs types.
Variable Sex Male Female Age (years) ≤ 60 > 60 Tumor size (mm) ≤ 20 > 20 Tumor location Upper Middle Lower Macroscopic type Elevated Flat Depressed Ulcer Presence Absence Depth of invasion Mucosa Submucosa Lymphovascular invasion Presence Absence Lymph node metastasis Presence Absence
Total (%)
SRCs group (%)
Non-SRCs group (%)
P-value 0.372
201 (62.9) 133 (37.1)
73 (63.5) 42 (36.5)
128 (54.4) 91 (41.5)
221 (66.2) 113 (33.8)
62 (53.9) 53 (46.1)
119 (54.3) 100 (45.7)
162 (48.5) 172 (51.5)
58 (50.4) 57 (49.6)
104 (47.5) 115 (52.5)
20 (6.0) 79 (23.7) 235 (70.3)
5 (4.3) 30 (26.1) 80 (69.6)
15 (6.8) 49 (22.4) 155 (70.8)
36 (10.8) 70 (21.0) 228 (68.2)
8 (7.0) 15 (13.0) 92 (80.0)
16 (7.3) 50 (22.8) 153 (69.9)
118 (35.3) 216 (64.7)
18 (15.7) 97 (84.3)
100 (45.7) 119 (54.3)
170 (50.9) 164 (49.1)
63 (54.8) 52 (45.2)
117 (53.4) 102 (46.6)
18 (5.4) 316 (94.6)
8 (7.0) 107 (93.0)
10 (4.6) 209 (95.4)
48 (14.4) 286 (85.6)
9 (8.5) 106 (91.5)
39 (17.8) 180 (82.2)
0.849
0.609
0.537
0.092
0.001
0.813
0.358
0.005
Statistical analysis Statistical analysis were performed with SPSS software, version 15.0 for Windows (SPSS Inc., Chicago, IL, USA). Results were given as percentages, mean and standard deviations, or median and ranges. Quantitative and qualitative variables were compared with the Student t test and 2 test, respectively. Overall survival data were analyzed using the Kaplan-Meier method. The log-rank test was used to compare survival curves. The Cox proportional hazards regression model was used to identify prognostic factors. Step-forward regression was used to build a valid statistical model for the association of prognostic factors with overall survival among patients. P-value of less than 0.05 was considered statistically significant.
(P = 0.358) were similar between the SRCs and non-SRCs groups.
Recurrence Locoregional recurrence included cancer recurrence within the regional resection area, local anastomotic sites, or peritoneal recurrence. A peritoneal recurrence was any recurrence within the abdominal cavity resulting in intraperitoneal implantation. Distant recurrence included liver metastasis, metastasis at other extra-abdominal sites, and nodal metastasis beyond the regional nodes. In the SRCs group, recurrence occurred for 12 patients, 7 of whom died. In the non-SRCs group, recurrence occurred for 43 patients, 31 of whom died. The incidence of recurrence for SRCs group was significantly lower than that for non-SRCs group (10.4% vs 19.6%; P < 0.05).
Results
Survival
Clinicopathologic features
The overall 5-year survival rate was 88.6% in all cases. The overall survival rate of patients in SRCs group was significantly better than that of patients in non-SRCs group (5-year survival, 93.9% vs 85.8%; P = 0.027). Univariate analysis of overall 5-year survival showed that SRCs subtype, lymphovascular invasion, and lymph node metastasis significantly affected patient prognosis (Table 2). The multivariate Cox proportional regression analysis revealed that SRCs subtype, lymphovascular invasion, and lymph node metastasis were independent prognostic factors (Table 3).
We compared the clinicopathologic features of patients with different histologic types of cancer (Table 1). The two groups were comparable for age and sex. Despite more frequent ulcer findings and the presence of lymph node metastasis ([15.7% vs 45.7%; P = 0.001]; [6.9% vs 18.3%; P = 0.005]) in the non-SRCs group, tumor size (P = 0.609), tumor location (P = 0.537), macroscopic type (P = 0.092), depth of invasion (P = 0.813), and lymphovascular invasion
360 Table 2
Z. Wang et al. Univariate analysis of factors related to the prognosis of early gastric cancer.
Factor SRCs subtype No Yes Sex Male Female Age(years) ≤ 60 > 60 Tumor Size (mm) ≤ 20 > 20 Tumor Location Upper Middle Lower Macroscopic Type Elevated Flat Depressed Ulcer Presence Absence Depth of Invasion Mucosa Submucosa Lymphovascular invasion Presence Absence Lymph node metastasis Presence Absence
Table 3
n
5-year survival rate (%)
219 115
85.8 93.9
201 133
89.6 87.2
221 113
90.5 84.9
162 172
90.1 87.2
20 79 235
85.0 88.6 88.9
36 70 228
88.9 88.5 88.6
118 216
84.7 90.7
170 164
91.8 85.4
18 316
72.2 89.6
48 286
79.2 90.2
P-value 0.027
0.511
0.131
0.402
0.868
0.999
0.099
0.066
0.024
0.026
Cox multiple regression analysis of overall survival.
Factor
Regression coefficient
Standard error
Hazard ratio (95% CI)
P-value
SRC type Ulcer Submucosal Invasion Lymphovascular invasion Lymph node metastasis
1.182 0.912 0.725 0.610 1.542
0.243 0.661 0.615 0.749 0.314
2.142 7.284 1.997 2.001 2.243
0.001 0.374 0.102 0.010 0.005
Discussion Gastric carcinoma is the major cause of cancer related deaths in China. The prognosis is different between early and advanced gastric cancer. Previous study identified that histologic type was one of the significant factors predicting prognosis [11]. Tumors with undifferentiated findings on histological examination are generally thought to have greater incidence of lymph node metastases and have a poor prognosis. Many studies included SRCs as a subgroup of undifferentiated carcinomas for analyzing, however, the clinicopathologic features and the prognosis of SRCs remain controversial. It has been reported that the majority of gastric cancers with SRC histologic subtype were diagnosed at an advanced stage, peritoneal carcinomatosis was significantly more frequent in SRC patients, and consequently leading to poorer prognosis. Piessen et al. [12] have shown that compared with non-SRC tumors, SRC is an independent
(2.011—5.234) (3.463—8.425) (2.556—7.547) (1.023—3.245) (1.871—4.259)
predictor of poor prognosis after R0 resection. The SRC group fared worse in both early-stage and late-stage groups. Recently, some authors reported that SRC has similar or better prognosis compared with other histologic subtypes in early stages of gastric cancers. Taghavi et al. [13] found that SRC portends a similar prognosis at all stages compared with a heterogeneous group of non-SRC gastric adenocarcinomas. Another study found no difference of the prognostic significance of SRC in stage-stratified mortality between SRC and well-differentiated groups [14]. So, the prognostic significance of signet ring gastric cancer needs clarification. In this study, we showed that SRC lesions had a significantly lower incidence of lymph node metastasis and exhibit favorable prognosis when diagnosed in early stage after surgery. Also, the incidence of recurrence for SRCs was lower than that for non-SRCs. In our study, SRCs were more frequently observed in younger patients compared with non-SRCs. Some reports
Early gastric cancer with signet ring cell histology assumed that better survival may be related to the younger age that is common in SRC patients [15]. Ulceration was more frequently found in non-SRCs group. It has been reported that ulcerative finding is one of the independent factors predicting more lymph node metastasis and worse survival in several studies [16,17]. It has been reported that SRC tumors show tendencies to be larger and to spread superficially to mucosal layers, but our study did not find this result. More and more evidence suggests that gastric cancer is a heterogeneous disease whose behavior is dependent on tumor histopathology. The presence of SRC histology should not be uniformly considered a poor prognostic feature. SRC familial syndrome linked to the CDH1 gene mutation. Early SRCs are characterized by a latent state with low aggressiveness, in contrast, when SRC has invaded the muscular layer, an accelerated tumor process leads to diffuse tumor invasiveness, associated with a greater risk of spread to lymph nodes and peritoneal surfaces and is linked to poor chemosensitivity and prognosis [18]. In our study, SRCs had a significantly lower incidence of lymph node metastasis and a significantly better prognosis. These data does raise the question of whether local therapy such as endoscopic resection for early gastric cancer with SRC would provide equivalent results. Endoscopic treatment deserves to be concerned about and should be investigated in further analyses. Because our research was a retrospective study in single institution with relatively smaller cases, it is reasonable to expect that useful information could be obtained by large-scale prospective studies. In summary, the present study demonstrated that despite SRC tumors being classified as undifferentiated, their behavior differed compared with poorly differentiated adenocarcinoma and mucinous adenocarcinoma tumors. SRCs had a significantly lower incidence of lymph node metastasis and a significantly better prognosis in early stage. Our findings have important prognostic implications that may improve treatment and follow-up strategies after radical surgery.
Disclosure of interest The authors declare that they have no competing interest.
References [1] Murakami T. Pathomorphological diagnosis. Definition and gross classification of early gastric cancer. Gann Monogr Cancer Res 1971;11(3):53—5.
361 [2] Kitamura K, Yamaguchi T, Taniguchi H, Hagiwara A, Sawai K, Takahashi T. Analysis of lymph node metastasis in early gastric cancer: rationale of limited surgery. J Surg Oncol 1997;64(1):42—7. [3] Kunisaki C, Shimada H, Nomura M, Akiyama H. Appropriate lymph node dissection for early gastric cancer based on lymph node metastases. Surgery 2001;129(2):153—7. [4] Sano T, Kobori O, Muto T. Lymph node metastasis from early gastric cancer: endoscopic resection of tumour. Br J Surg 1992;79(3):241—4. [5] Maruyama K, Kaminishi M, Hayashi K-I, et al. Gastric cancer treated in 1991 in Japan: data analysis of nationwide registry. Gastric cancer 2006;9(2):51—66. [6] Lee S, Park J, Han S, et al. 2004 Nationwide Gastric Cancer Report in Korea. J Korean Gastric Cancer Assoc 2007;7(1):47—54. [7] Japanese Gastric Cancer A. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011;14(2):101—12. [8] Hamilton SR, Aaltonen LA. Pathology and genetics of tumours of the digestive system. Lyon: IARC press; 2000. [9] Otsuji E, Yamaguchi T, Sawai K, Takahashi T. Characterization of signet ring cell carcinoma of the stomach. J Surg Oncol 1998;67(4):216—20. [10] Maehara Y, Sakaguchi Y, Moriguchi S, et al. Signet ring cell carcinoma of the stomach. Cancer 1992;69(7):1645—50. [11] Katai H, Sano T. Early gastric cancer: concepts, diagnosis, and management. Int J Clin Oncol 2005;10(6):375—83. [12] Piessen G, Messager M, Leteurtre E, Jean-Pierre T, Mariette C. Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation. Ann Surg 2009;250(6):878—87. [13] Taghavi S, Jayarajan SN, Davey A, Willis AI. Prognostic significance of signet ring gastric cancer. J Clin Oncol 2012;30(28):3493—8. [14] Theuer CP, Nastanski F, Brewster WR, Butler JA, Anton-Culver H. Signet ring cell histology is associated with unique clinical features but does not affect gastric cancer survival. Am Surg 1999;65(10):915—21. [15] Messager M, Lefevre JH, Pichot-Delahaye V, et al. The impact of perioperative chemotherapy on survival in patients with gastric signet ring cell adenocarcinoma: a multicenter comparative study. Ann Surg 2011;254(5):684—93 [discussion 693]. [16] Gotoda T, Yanagisawa A, Sasako M, et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer 2000;3(4):219—25. [17] Li C, Kim S, Lai JF, et al. Risk factors for lymph node metastasis in undifferentiated early gastric cancer. Ann Surg Oncol 2008;15(3):764—9. [18] Gronnier C, Messager M, Robb WB, et al. Is the negative prognostic impact of signet ring cell histology maintained in early gastric adenocarcinoma? Surgery 2013;154(5):1093—9.
Available online at
ScienceDirect www.sciencedirect.com
ORIGINAL ARTICLE
Clinicopathological features and outcomes in patients undergoing radical resection for early gastric cancer with signet ring cell histology Z. Wang , X. Zhang , J. Hu , W. Zeng , Z. Zhou ∗ Cancer Hospital of the Chinese Academy of Medical Sciences, Peking Union Medical College, the Department of Abdominal Surgical Oncology, Beijing, China Available online 23 October 2015
KEYWORDS Early gastric cancer; Signet ring cell histology; Prognosis
Summary Background: The signet ring cell histology is regarded as an independent predictor of poor prognosis in advanced gastric adenocarcinomas, but its biologic behavior in early gastric cancer remains highly controversial. Objective: Our objective was to compare the clinicopathological features and outcomes in patients undergoing curative resection between SRCs and non-SRCs histologic types of early gastric cancer. Methods: Clinicopathologic features and the overall survival rates of 334 patients with early gastric cancer undergoing D2 curative resection from January 1994 to December 2008 were retrospectively reviewed and compared according to the histologic type. Results: Clinicopathologic features were comparable between two groups, except age, ulcer findings and the presence of lymph node metastasis. The incidence of recurrence for SRCs group was significantly lower than that for non-SRCs group (10.4% vs 19.6%; P < 0.05). The overall 5-year survival rate was 88.6% in all cases. The overall survival rate of patients in SRCs group was significantly better than that of patients in non-SRCs group (5-year survival, 93.9% vs 85.8%; P = 0.027). Multivariable analysis revealed that SRCs subtype, lymphovascular invasion, and lymph node metastasis were independent prognostic factors. Conclusion: Our analysis revealed that the biological behavior of SRCs was different from other undifferentiated cancer histologic subtypes in early stage. Early gastric cancer with signet ring cell histology had low incidence of lymph node metastasis and a relatively favorable prognosis. © 2015 Elsevier Masson SAS. All rights reserved.
Introduction ∗
Corresponding author. E-mail address: [email protected] (Z. Zhou).
http://dx.doi.org/10.1016/j.jviscsurg.2015.09.021 1878-7886/© 2015 Elsevier Masson SAS. All rights reserved.
In 1962, the Japanese Society of Gastroenterological Endoscopy defined early gastric cancer as a lesion confined
358 to the mucosa and/or submucosa, regardless of lymph node metastatic status [1]. The need to define this category of gastric cancer is related to the difference in prognosis between early and advanced gastric cancer. The prognosis is generally favorable in early gastric cancers after radical surgery, with a 5-year survival rate of more than 90% [2,3]. The proportion of early gastric cancer among all gastric cancers has increased to nearly 50% in Japan and Korea [4—6]. With more widespread mass screenings, as well as advances in endoscopic techniques and equipment, similar trends have been observed during the past few decades in China. According to the Japanese Gastric Cancer Association, undifferentiated gastric carcinoma includes poorly differentiated adenocarcinoma, mucinous adenocarcinoma and signet ring cell carcinoma [7]. Signet ring cell carcinomas (SRCs) are defined as gastric cancers in which the predominant component consists of isolated or small groups of malignant cells containing intracytoplasmic mucins [8]. Generally, SRCs and poorly differentiated adenocarcinomas, mucinous adenocarcinoma are associated with an ominous outcome. However, the prognostic significance of SRCs histologic subtype in early stage remains controversial. Some studies have reported that SRCs have a lower incidence of lymph node metastasis and favorable prognosis than other undifferentiated cancer histologic subtypes [9,10]. For this reason, undifferentiated early gastric carcinoma includes SRCs subtype and non-SRCs subtype should be investigated separately with regard to oncologic outcomes. The aim of this retrospective study was to compare the clinicopathologic features and outcomes between SRCs group and non-SRCs group in patients undergoing radical resection for early gastric cancer.
Patients and methods Patients Institutional review board approval was obtained before conducting this study. A total of 334 patients who had undergone radical (R0) gastrectomy with D2 lymph node dissection for histologically proven undifferentiated early gastric cancer from January 1994 to December 2008 at the Department of Abdominal Surgical Oncology, Cancer Hospital of the Chinese Academy of Medical Sciences, Peking Union Medical College were selected for this study. Cases with recurrence or multifocal gastric cancer were excluded. Histology was classified according to the Japanese Gastric Cancer Association [7]. All the patients routinely underwent an upper alimentary tract barium meal and electronic gastroscope examination before surgery to identify the diseased region and the pathologic type to confirm the diagnosis of malignant neoplasm of the stomach after pathologic examination. The preoperative routine chest X-ray, abdominal ultrasound, and upper abdominal CT examination showed no pulmonary, hepatic, or other distant metastases and no tumor directly invading the pancreas, spleen, liver, or colon. Endoscopic ultrasound examination was not performed routinely. All patients underwent radical subtotal or total gastrectomies, depending on the tumor location and intraoperative verification of tumor-free resection margins, as well as D2 lymphadenectomies. Those with tumors located in the lower third of the stomach underwent distal gastrectomy. Patients with tumors in the middle third of the stomach underwent either distal
Z. Wang et al. gastrectomy or total gastrectomy according to the direction of the tumor invasion. Proximal gastrectomy was used for patients with tumors in the upper third of the stomach, and total gastrectomy was used for those with tumors occupying the entire stomach. In this series, distal gastrectomy was performed in 283 patients, total gastrectomy was performed in 33 patients, and proximal gastrectomy was performed in 18 patients. No patient has received neoadjuvant therapy before surgery. The methods of reconstruction after distal gastrectomy include Billroth I, II or Roux-enY. Roux-en-Y reconstruction and jejunal interposition are the most common methods used after a total gastrectomy. All specimens were examined after resection. World Health Organization criteria for histological typing of gastric tumors were used, where signet ring cell carcinoma is defined as an adenocarcinoma in which a predominant component (more than 50% of the tumor) is made up of isolated or small groups of malignant cells containing intracytoplasmic mucin. The formalin-fixed specimens were cut into multiple slices, principally parallel to the lesser curvature, at an interval of 3 mm. The hematoxylin and eosin stained sections of tumor were examined. A single pathologist retrieved all lymph nodes by palpation under gross inspection. The lymph nodes were cut into two pieces along the long axis, embedded in paraffin blocks, and stained with haematoxylin and eosin. Of these patients, SRCs group had 115 patients (34.4%), and non-SRCs had 219 patients (65.6%). The patients’ clinical characteristics, histopathological parameters and followup data were analyzed. Clinicopathological factors, such as sex-ratio, age, tumor size, tumor location, macroscopic appearance, histological type, ulceration, depth of tumor invasion, lymph node status and lymphovascular invasion were defined according to the Japanese Classification of Gastric Carcinoma [7]. The maximum diameter of tumor was recorded as tumor size. Macroscopic type includes elevated (I, protruded; IIa, superficial elevated), flat (IIb, superficial flat), and depressed (IIc, superficial depressed; III, excavated). Lesions with ulceration or scarring from previous ulceration (converging folds or deformity of the muscularis propria, or fibrosis in the submucosal or deeper layer) within them were regarded as ulcerated lesions. The depth of tumor invasion was classified as mucosa and submucosa carcinoma. Lymphovascular invasion was defined as the presence of tumor emboli either in the lymphatic duct or the vascular lumen. Overall survival and the pattern of recurrence were compared between the two groups. Patients with SRCs were considered as the reference group for statistical analysis.
Follow-up All patients who survived the operation were followed until death or the cutoff date (March 31, 2014). All patients were followed up regularly at 3-month intervals in the first 2 years and the every 6 months thereafter for clinical examination including chest X-ray, abdominal and pelvic ultrasound or CT and tumor markers. Follow-up evaluation was implemented by means of outpatient service, telephone calls, and letters. Median follow-up period were 97 months (range, 66—236). Only deaths due to early gastric cancer were considered. Deaths due to other causes were censored at the date of death. Three patients were lost to follow-up. These patients were excluded from the present study.
Early gastric cancer with signet ring cell histology Table 1
359
Comparison of clinicopathologic features between patients with SRCs and non-SRCs types.
Variable Sex Male Female Age (years) ≤ 60 > 60 Tumor size (mm) ≤ 20 > 20 Tumor location Upper Middle Lower Macroscopic type Elevated Flat Depressed Ulcer Presence Absence Depth of invasion Mucosa Submucosa Lymphovascular invasion Presence Absence Lymph node metastasis Presence Absence
Total (%)
SRCs group (%)
Non-SRCs group (%)
P-value 0.372
201 (62.9) 133 (37.1)
73 (63.5) 42 (36.5)
128 (54.4) 91 (41.5)
221 (66.2) 113 (33.8)
62 (53.9) 53 (46.1)
119 (54.3) 100 (45.7)
162 (48.5) 172 (51.5)
58 (50.4) 57 (49.6)
104 (47.5) 115 (52.5)
20 (6.0) 79 (23.7) 235 (70.3)
5 (4.3) 30 (26.1) 80 (69.6)
15 (6.8) 49 (22.4) 155 (70.8)
36 (10.8) 70 (21.0) 228 (68.2)
8 (7.0) 15 (13.0) 92 (80.0)
16 (7.3) 50 (22.8) 153 (69.9)
118 (35.3) 216 (64.7)
18 (15.7) 97 (84.3)
100 (45.7) 119 (54.3)
170 (50.9) 164 (49.1)
63 (54.8) 52 (45.2)
117 (53.4) 102 (46.6)
18 (5.4) 316 (94.6)
8 (7.0) 107 (93.0)
10 (4.6) 209 (95.4)
48 (14.4) 286 (85.6)
9 (8.5) 106 (91.5)
39 (17.8) 180 (82.2)
0.849
0.609
0.537
0.092
0.001
0.813
0.358
0.005
Statistical analysis Statistical analysis were performed with SPSS software, version 15.0 for Windows (SPSS Inc., Chicago, IL, USA). Results were given as percentages, mean and standard deviations, or median and ranges. Quantitative and qualitative variables were compared with the Student t test and 2 test, respectively. Overall survival data were analyzed using the Kaplan-Meier method. The log-rank test was used to compare survival curves. The Cox proportional hazards regression model was used to identify prognostic factors. Step-forward regression was used to build a valid statistical model for the association of prognostic factors with overall survival among patients. P-value of less than 0.05 was considered statistically significant.
(P = 0.358) were similar between the SRCs and non-SRCs groups.
Recurrence Locoregional recurrence included cancer recurrence within the regional resection area, local anastomotic sites, or peritoneal recurrence. A peritoneal recurrence was any recurrence within the abdominal cavity resulting in intraperitoneal implantation. Distant recurrence included liver metastasis, metastasis at other extra-abdominal sites, and nodal metastasis beyond the regional nodes. In the SRCs group, recurrence occurred for 12 patients, 7 of whom died. In the non-SRCs group, recurrence occurred for 43 patients, 31 of whom died. The incidence of recurrence for SRCs group was significantly lower than that for non-SRCs group (10.4% vs 19.6%; P < 0.05).
Results
Survival
Clinicopathologic features
The overall 5-year survival rate was 88.6% in all cases. The overall survival rate of patients in SRCs group was significantly better than that of patients in non-SRCs group (5-year survival, 93.9% vs 85.8%; P = 0.027). Univariate analysis of overall 5-year survival showed that SRCs subtype, lymphovascular invasion, and lymph node metastasis significantly affected patient prognosis (Table 2). The multivariate Cox proportional regression analysis revealed that SRCs subtype, lymphovascular invasion, and lymph node metastasis were independent prognostic factors (Table 3).
We compared the clinicopathologic features of patients with different histologic types of cancer (Table 1). The two groups were comparable for age and sex. Despite more frequent ulcer findings and the presence of lymph node metastasis ([15.7% vs 45.7%; P = 0.001]; [6.9% vs 18.3%; P = 0.005]) in the non-SRCs group, tumor size (P = 0.609), tumor location (P = 0.537), macroscopic type (P = 0.092), depth of invasion (P = 0.813), and lymphovascular invasion
360 Table 2
Z. Wang et al. Univariate analysis of factors related to the prognosis of early gastric cancer.
Factor SRCs subtype No Yes Sex Male Female Age(years) ≤ 60 > 60 Tumor Size (mm) ≤ 20 > 20 Tumor Location Upper Middle Lower Macroscopic Type Elevated Flat Depressed Ulcer Presence Absence Depth of Invasion Mucosa Submucosa Lymphovascular invasion Presence Absence Lymph node metastasis Presence Absence
Table 3
n
5-year survival rate (%)
219 115
85.8 93.9
201 133
89.6 87.2
221 113
90.5 84.9
162 172
90.1 87.2
20 79 235
85.0 88.6 88.9
36 70 228
88.9 88.5 88.6
118 216
84.7 90.7
170 164
91.8 85.4
18 316
72.2 89.6
48 286
79.2 90.2
P-value 0.027
0.511
0.131
0.402
0.868
0.999
0.099
0.066
0.024
0.026
Cox multiple regression analysis of overall survival.
Factor
Regression coefficient
Standard error
Hazard ratio (95% CI)
P-value
SRC type Ulcer Submucosal Invasion Lymphovascular invasion Lymph node metastasis
1.182 0.912 0.725 0.610 1.542
0.243 0.661 0.615 0.749 0.314
2.142 7.284 1.997 2.001 2.243
0.001 0.374 0.102 0.010 0.005
Discussion Gastric carcinoma is the major cause of cancer related deaths in China. The prognosis is different between early and advanced gastric cancer. Previous study identified that histologic type was one of the significant factors predicting prognosis [11]. Tumors with undifferentiated findings on histological examination are generally thought to have greater incidence of lymph node metastases and have a poor prognosis. Many studies included SRCs as a subgroup of undifferentiated carcinomas for analyzing, however, the clinicopathologic features and the prognosis of SRCs remain controversial. It has been reported that the majority of gastric cancers with SRC histologic subtype were diagnosed at an advanced stage, peritoneal carcinomatosis was significantly more frequent in SRC patients, and consequently leading to poorer prognosis. Piessen et al. [12] have shown that compared with non-SRC tumors, SRC is an independent
(2.011—5.234) (3.463—8.425) (2.556—7.547) (1.023—3.245) (1.871—4.259)
predictor of poor prognosis after R0 resection. The SRC group fared worse in both early-stage and late-stage groups. Recently, some authors reported that SRC has similar or better prognosis compared with other histologic subtypes in early stages of gastric cancers. Taghavi et al. [13] found that SRC portends a similar prognosis at all stages compared with a heterogeneous group of non-SRC gastric adenocarcinomas. Another study found no difference of the prognostic significance of SRC in stage-stratified mortality between SRC and well-differentiated groups [14]. So, the prognostic significance of signet ring gastric cancer needs clarification. In this study, we showed that SRC lesions had a significantly lower incidence of lymph node metastasis and exhibit favorable prognosis when diagnosed in early stage after surgery. Also, the incidence of recurrence for SRCs was lower than that for non-SRCs. In our study, SRCs were more frequently observed in younger patients compared with non-SRCs. Some reports
Early gastric cancer with signet ring cell histology assumed that better survival may be related to the younger age that is common in SRC patients [15]. Ulceration was more frequently found in non-SRCs group. It has been reported that ulcerative finding is one of the independent factors predicting more lymph node metastasis and worse survival in several studies [16,17]. It has been reported that SRC tumors show tendencies to be larger and to spread superficially to mucosal layers, but our study did not find this result. More and more evidence suggests that gastric cancer is a heterogeneous disease whose behavior is dependent on tumor histopathology. The presence of SRC histology should not be uniformly considered a poor prognostic feature. SRC familial syndrome linked to the CDH1 gene mutation. Early SRCs are characterized by a latent state with low aggressiveness, in contrast, when SRC has invaded the muscular layer, an accelerated tumor process leads to diffuse tumor invasiveness, associated with a greater risk of spread to lymph nodes and peritoneal surfaces and is linked to poor chemosensitivity and prognosis [18]. In our study, SRCs had a significantly lower incidence of lymph node metastasis and a significantly better prognosis. These data does raise the question of whether local therapy such as endoscopic resection for early gastric cancer with SRC would provide equivalent results. Endoscopic treatment deserves to be concerned about and should be investigated in further analyses. Because our research was a retrospective study in single institution with relatively smaller cases, it is reasonable to expect that useful information could be obtained by large-scale prospective studies. In summary, the present study demonstrated that despite SRC tumors being classified as undifferentiated, their behavior differed compared with poorly differentiated adenocarcinoma and mucinous adenocarcinoma tumors. SRCs had a significantly lower incidence of lymph node metastasis and a significantly better prognosis in early stage. Our findings have important prognostic implications that may improve treatment and follow-up strategies after radical surgery.
Disclosure of interest The authors declare that they have no competing interest.
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