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Predictive factors for lymph node metastasis inearly gastric cancer with signet ring cell histologyand their impact on the surgical strategy: analysisof single institutional experience

Zheng Wang, MD, Xingmao Zhang, MD, Junjie Hu, MD, Weigen Zeng, MD,Jianwei Liang, MD, Haitao Zhou, MD, and Zhixiang Zhou, MD*

Department of Abdominal Surgical Oncology, Cancer Hospital of the Chinese Academy of Medical Sciences, Peking

Union Medical College, Beijing, P.R.China

a r t i c l e i n f o

Article history:

Received 18 December 2013

Received in revised form

19 March 2014

Accepted 21 March 2014

Available online xxx

Keywords:

Early gastric cancer

Signet ring cell carcinoma

Lymph node metastasis

Endoscopic treatment

* Corresponding author. Department of AbdPeking Union Medical College, Nanli 17, Pan

E-mail address: zhouzx2014@gmail.com0022-4804/$ e see front matter ª 2014 Elsevhttp://dx.doi.org/10.1016/j.jss.2014.03.065

a b s t r a c t

Background: The prognosis of early gastric cancer (EGC) with signet ring cell histology is

more favorable than other undifferentiated gastric adenocarcinomas. An accurate

assessment of potential lymph node metastasis is important for the appropriate treatment

of EGC with signet ring cell histology. Therefore, this study analyzed the predictive factors

associated with lymph node metastasis in patients with this type of EGC.

Methods: A total of 136 EGC with signet ring cell histology patients who underwent D2

radical gastrectomy were reviewed in this study. The clinicopathologic features were

analyzed to identify predictive factors for lymph node metastasis.

Results: The overall rate of lymph node metastasis in EGC with signet ring cell histology was

10.3%. Using a univariate analysis, the risk factors for lymph node metastasis were iden-

tified as the tumor size, depth of tumor invasion, and lymphovascular invasion. The

multivariate analysis revealed that tumor size >2 cm, submucosal invasion, and lym-

phovascular invasion were independent risk factors of lymph node metastasis (P < 0.05).

Conclusions: The risk of lymph node metastasis of EGC with signet ring cell histology was

high in those with tumor sizes �2 cm, submucosal tumors, and lymphovascular invasion.

A minimally invasive treatment, such as endoscopic resection, might be possible in highly

selective cases of EGC with signet ring cell histology with intramucosal invasion, tumor

size <2 cm, and no lymphovascular invasion.

ª 2014 Elsevier Inc. All rights reserved.

1. Introduction node metastasis and a favorable outcome after surgery [2].

In 1962, the Japanese Society of Gastroenterological Endos-

copy defined early gastric cancer (EGC) as a lesion confined to

the mucosa and/or submucosa, regardless of lymph node

metastatic status [1]. EGCs have a low incidence of lymph

ominal Surgical Oncologyjiayuan Road, Chaoyang(Z. Zhou).ier Inc. All rights reserved

Although radical gastrectomy including lymph node dissec-

tion has been recognized as the standard surgical operation

for EGC, unnecessary surgery could be avoided and endo-

scopic treatment might be a consideration in patients with

EGC with negligible risk of lymph node metastasis.

, Cancer Hospital of the Chinese Academy of Medical Sciences,District, Beijing 100021, P.R.China. Tel./fax: þ86 010 8778 7110.

.

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1e42

Many investigations have shown that patients with EGC

with signet ring cell histology have amore favorable prognosis

than patients with other undifferentiated gastric adenocarci-

nomas, because EGCwith signet ring cell histology has a lower

probability of lymph node metastasis [3]. Consequently, it

might be considered as an indication of endoscopic surgery.

However, the feasibility of endoscopic treatment for this type

of EGC is still in debate.

The present retrospective study was designed to evaluate

the factors that can be predicted the presence of lymph node

metastasis with signet ring cell histology of EGC. Using these

predictive factors, we established suitable criteria to elucidate

which subgroup of EGC with signet ring cell histology patients

could be treated with endoscopic treatment instead of radical

surgery.

2. Patients and methods

This study enrolled 136 EGC with signet ring cell histology

patients, those were pathologically proven after curative

gastrectomywith lymph node dissection from January 1994 to

December 2012 at the Department of Abdominal Surgical

Oncology, Cancer Hospital of the Chinese Academy of Medical

Sciences, Peking Union Medical College.

All the patients routinely underwent an upper alimentary

tract barium meal and electronic gastroscope examination

before surgery to identify the diseased region and the patho-

logic 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 computed tomography (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 intra-

operative verification of tumor-free resection margins and D2

lymphadenectomies. No patient has received neoadjuvant

therapy before surgery. The methods of reconstruction after

distal gastrectomy include Billroth I, II, or Roux-en-Y. Roux-

en-Y reconstruction and jejunal interposition are the most

common methods used after a total gastrectomy. All speci-

mens were examined after resection. World Health Organi-

zation criteria for histologic typing of gastric tumours were

used, where signet ring cell carcinoma is defined as an

adenocarcinoma in which a predominant component (more

than 50% of the tumour) ismade up of isolated or small groups

of malignant cells containing intracytoplasmic mucin [4]. A

single pathologist retrieved all lymph nodes by palpation

under gross inspection. No size limitation was imposed for

lymph node harvesting. The lymph nodes were cut into two

pieces along the long axis, embedded in paraffin blocks, and

stainedwith haematoxylin and eosin. The status of the lymph

nodes was not evaluated by immunohistochemistry.

The patients’ clinical characteristics and histopathologic

parameters were analyzed. Clinicopathologic factors, such

as gender, age, tumor size, tumor location, macroscopic

appearance, depth of tumor invasion, ulceration, lympho-

vascular invasion and lymph node status, were defined

according to the General Rules of the Japanese Classification

of Gastric Carcinoma (second English edition) [5]. The

maximum diameter of tumor was recorded as tumor size.

Macroscopic type included elevated (I, protruded and IIa, su-

perficial elevated), flat (IIb, superficial flat), depressed (IIc,

superficial depressed and III, excavated). The depth of tumor

invasion was classified asmucosa and submucosa carcinoma.

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 [6]. Lymphovascular invasion

was defined as the presence of tumor emboli either in the

lymphatic duct or the vascular lumen.

2.1. Statistical analysis

Univariate andmultivariate analyses of risk factors associated

with lymph nodemetastasis were performed using the c2 test

and logistic regression models, respectively. P < 0.05 was

considered statistically significant. Statistical analyses were

performed with SPSS software, version 15.0 for Windows

(SPSS Inc, Chicago, IL).

3. Results

The study involved 91 men and 45 women, with a male-to-

female ratio of 2.02:1. The median age of the enrolled pa-

tients was 58 y (24e82 y). A total of 96 patients had tumors

located in the lower third of the stomach, 34 patients had

tumors in the middle third of the stomach, whereas six pa-

tients had tumors in the upper third of the stomach. Sixty nine

cases had tumors �2.0 cm in diameters, whereas 67 cases

were <2.0 cm. Tumor invasion was limited to the mucosal

layer in 79 patients, whereras in 57 patients, the tumors had

invaded the submucosal layer. Elevated-type tumors were

macroscopically observed in 10 patients, flat-type tumors

were observed in 18 patients, and depressed-type tumors

were observed in the remaining 108 patients. Twenty four

patients had ulcer finding. There were 18 cases of lympho-

vascular invasion.

The univariate analysis of factors predicting lymph node

metastasis is presented in Table 1. Tumor size, depth of tumor

invasion, and lymphovascular invasion were significantly

correlated with lymph node metastasis. There was no signif-

icant difference in gender, age, tumor location, macroscopic

type, and ulceration. The multivariate analysis revealed that

tumor size �2.0 cm, submucosal invasion, and lymphovas-

cular invasion were independent risk factors associated with

lymph node metastasis (Table 2). To identify the subgroup of

patients who could be amenable to endoscopic treatment, the

lymph node metastasis in EGC with signet ring cell histology

cases were evaluated according to the depth of invasion,

tumor size, and the presence of lymphovascular invasion

(Table 3). The numbers in parentheses represent the number

and percentage of cases with lymph nodemetastasis. None of

the 59 patients with a mucosa-confined tumor <20 mm in

diameter and no lymphovascular invasion showed lymph

node metastasis. No lymph node metastasis was observed in

five patients with submucosal tumors <2.0 cm in diameter

Table 1 e Risk factors for lymph node metastasis byunivariate analysis.

Factor N Lymph nodemetastasis (%)

c2 Pvalue

Gender

Male 91 9 (9.9) 0.049 0.825

Female 45 5 (11.1)

Age (y)

�60 74 8 (10.8) 0.047 0.828

>60 62 6 (9.7)

Tumor location

Upper 6 1 (16.7) 0.431 0.806

Middle 34 4 (11.8)

Lower 96 9 (9.4)

Tumor size (cm)

<2.0 67 2 (3.0) 7.640 0.006

�2.0 69 12 (17.4)

Depth of invasion

Mucosal 79 3 (3.8) 8.615 0.003

Submucosal 57 11 (19.3)

Macroscopic type

Elevated 10 1 (10.0) 0.015 0.992

Flat 18 2 (11.1)

Depressed 108 11 (10.2)

Ulcer

Presence 24 5 (20.8) 3.505 0.061

Absence 112 9 (8.0)

Lymphovascular invasion

Positive 18 8 (44.4) 26.200 0.001

Negative 118 6 (5.1)

Table 3 e Relationship between the three independentpredictive factors (depth of invasion, tumor size, andLymphovascular invasion) and the incidence of nodemetastasis.

Depth of invasion Tumorsize

Lymphovascularinvasion

Lymph nodemetastasisrate (%)

Mucosal <2.0 Negative 0 (0/59)

<2.0 Positive 100 (1/1)

�2.0 Negative 5.6 (1/18)

�2.0 Positive 100 (1/1)

Submucosal <2.0 Negative 0 (0/5)

<2.0 Positive 50 (1/2)

�2.0 Negative 13.9 (5/36)

�2.0 Positive 35.7 (5/14)

j o u rn a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1e4 3

with no lymphovascular invasion, but it is not statistically

significant because of the limited sample size.

4. Discussion

Gastric carcinoma is the major cause of cancer-related deaths

in China. The prognosis is different between early and

advanced gastric cancer. The average 5-y survival rate in pa-

tients with EGC is >90%, and it is up to 94.2% in patients

without lymphnodemetastasis [7]. Treatment options for EGC

include endoscopic resection, wedge resection, laparoscopi-

cally assisted gastrectomy, and open gastrectomy [8e10].

Radical surgery with lymph node dissection has been the

standard treatment for EGC. Because long-term survival after

gastrectomy is excellent, considering the lower incidence of

lymph node metastasis, endoscopic techniques, such as

endoscopic mucosal resection or endoscopic submucosal

dissection (ESD), have been generally accepted as an alternate

treatment to improve the quality of life for selected patients.

Endoscopic surgery is technically used to dissect the mucosa

Table 2 e Risk factors for lymph node metastasis bymultivariate analysis.

Factor OR 95% CI P value

Tumor size �2.0 cm 4.32 3.17e7.24 0.023

Submucosal invasion 3.87 2.12e6.23 0.016

Lymphovascular invasion 9.21 6.53e15.25 0.007

or the submucosa layer, with regional lymph nodes left un-

treated; so, the probability of lymph node metastasis is a key

criterion for defining subgroup of patients for whom these

endoscopic methods are appropriate. Before operation, iden-

tification of lymphnodemetastasis can not be achieved via CT

or endoscopic ultrasonography because of the lack of reliable

criteria for metastatic nodes [11]. Bhandari et al. [12] reported

that the accuracy, sensitivity, and specificity of endoscopic

ultrasonography (EUS), and three-dimensional multidetector

row CT for lymph node staging was, respectively, 79.1%, 57%,

and 89.5%, and 75%; 57.4% and 89.3% for gastric cancer.

Tsendsuren et al. [13] reported that the overall diagnostic ac-

curacy of EUS in preoperative determination of gastric cancer

depth of invasion was 68.3% (41/28) and 83.3% (12/10), 60% (20/

12), 100% (5/5), and 25% (4/1) for T1, T2, T3, and T4, respec-

tively, and the diagnostic accuracy of metastatic lymph node

involvement or N staging of EUS was 100% (17/17) for N0 and

41.7% (24/10) for Nþ, respectively, and 66% (41/27) for overall.

For this reason, many tumor-related variables are currently

under investigation as predictors of lymph node involvement,

particularly in Japan and Korea.

Many recent studies have shown that EGC with signet ring

cell histology rarely metastasizes to lymph nodes and has been

associated with a favourable prognosis [14]. Lee et al. [15] re-

ported that in 1362 patients undergoing gastrectomy for EGC,

the rate of lymph node metastasis was similar for tumours

with signet ring cell and differentiated histologic findings

(10.7% versus 9,0% respectively; P ¼ 0.307). Park et al. [16] re-

ported that the incidence of lymph-to-node metastasis was

7.9%:1.9% with intramucosal cancer and 6% with submucosal

cancer for signet ring cell gastric cancer. There is a continuous

discussion concerning the indication for endoscopic treatment

in EGC with signet ring cell histology. In this analysis of a

consecutive series of EGC with signet ring cell histology cases

from a single institution, the rate of lymph node metastasis

was 10.3%. The frequency of lymph node metastasis in

mucosal cancers with signet ring cell histology was 3.8% (3 of

79), similar to the overall lymph node metastasis rate for EGCs

confined to the mucosa, regardless of histological type [8]. For

further investigation of the relationship between various clin-

icopathologic features and lymph node metastasis, we per-

formed univariate and multivariate analyses, and confirmed

that tumor size, lymphovascular invasion, and depth of

j o u r n a l o f s u r g i c a l r e s e a r c h x x x ( 2 0 1 4 ) 1e44

invasion were independent predictors of nodemetastasis. Kim

et al. [17] reported that early signet ring cell carcinoma with

mucosal invasion, size <15 mm, and no lymphatic invasion

had no LNM. Ha et al. [14] observed that independent risk fac-

tors for lymph node metastasis are large tumor dimension,

lymphatic involvement, and submucosal invasion.

According to the incidence of node metastasis, we propose

EGC with signet ring cell histology with intramucosal inva-

sion, and<2 cm in diameter without lymphovascular invasion

might be suitable for endoscopic surgery. The relationship

between the three independent predictive factors (depth of

invasion, tumor size, and lymphovascular invasion) and the

incidence of node metastasis were analyzed. No metastatic

lymph node was detected for EGC with signet ring cell his-

tology with mucosal invasion and <2 cm in diameter without

lymphovascular invasion, which indicate an extremely low

risk of node metastasis. Consequently, these cancers should

be considered as indications for endoscopic surgery to main-

tain a high quality of life. No lymph node metastasis was

observed in five patients with submucosal tumors <2.0 cm in

diameter with no lymphovascular invasion, but it is not sta-

tistical significance because of the limited sample size. For

other cancers, positive lymph nodes were frequently observed

and they should not be considered as indications of endo-

scopic surgery based on the results in the present study.

Similarly, Kang et al. [18] reported that complete endoscopic

resection was possible in most tumors �20 mm in size and in

intramucosal carcinomas, and no recurrence and no metas-

tasis occurred after ESD during a median follow-up period of

13 mo. However, use of ESD for EGC with signet ring cell his-

tology has only begun recently, because our research was a

retrospective study in single institution with smaller cases, it

is reasonable to expect that useful information could be ob-

tained by large-scale prospective studies.

5. Conclusions

In summary, prediction of lymph nodemetastasis in EGCwith

signet ring cell histology is very important to decide the

treatment strategies preoperatively. Endoscopic treatment

might be an alternative option in some carefully selected

mucosal, <2 cm in tumor size and without lymphovascular

invasion signet ring cell gastric cancer patients.

Acknowledgment

Authors’ contributions: Z.W. and Z.Z. contributed to concep-

tion and design. Z.W.,X.Z., J.H., W.Z., J.L., and H.Z. analyzed

and interpreted the data. Z.W.,X.Z., J.H., W.Z., J.L., and H.Z.

collected the data. Z.W.wrote the article. Z.Z.made the critical

revision of the article.

Disclosure

The authors reported no proprietary or commercial interest in

any product mentioned or concept discussed in this article.

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