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Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer
Asian Journal of Surgery xxx (xxxx) xxx
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Original Article
Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer Xiao-Qin Liang a, b, 1, Zhuo Wang b, 1, Hong-Tao Li c, 1, Gui Ma d, Wen-Wen Yu a, Hai-Cun Zhou a, Hong-Bin Liu a, c, * a
Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, Gansu Province, China Department of Pathology, Gansu Province People's Hospital, Lanzhou, 730000, Gansu Province, China Department of General Surgery, The 940th of Joint Logistics Support Force of the Chinese People's Liberation Army, Lanzhou, 730050, Gansu Province, China d Department of Pathology, Gansu Provincial Cancer Hospital, Lanzhou, 730050, Gansu Province, China b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 July 2019 Received in revised form 30 October 2019 Accepted 8 December 2019 Available online xxx
Background: Despite the risk of lymph node metastasis (LNM), the indications of endoscopic submucosal dissection (ESD) has expanded to undifferentiated type (UD-type) early gastric cancer (EGC). There is debate as to whether the endoscopic resection can be used. This study was conducted to evaluate risk factors for LNM in undifferentiated early gastric cancer, implications for the indication of the ESD so as to providing evidence for proper clinical management for UD-type EGC. Method: We retrospectively analyzed 203 patients with UD-type EGC who underwent gastrectomy for primary gastric adenocarcinoma between 2012 and 2017. We evaluated the relationship between the clinicopathological factors and the presence of LNM using univariable and multivariable logistic regression analyses. Results: A total of 203 UD-type EGC patients were enrolled, and LNM was positive in 40 cases (19.7%). Multivariable logistic regression analysis identified three independent risk factors for LNM, the tumor size (2.0 cm, P < 0.001), depth of invasion (P < 0.001), and lymphatic vessel involvement (LVI, P < 0.001). LNM was observed in 5.9% patients without the three predictive factors in UD-type EGC, whereas 7.7% and 37.7% of patients with one and two risk factors had LNM, respectively. In contrast, the LNM rate was up to be 66.7% in patients with three factors. Of 41 patients satisfying the expanded indication of ESD, 3 patients (7.3%) showed LNM. LNM was not found in any of 12 patients with small intramucosal lesions (<1.0 cm) without LVI. Conclusions: LNM-related risk factors were tumor larger than 2.0 cm, submucosal invasion, and the presence of LVI in UD-type EGC. ESD alone may be sufficient treatment for the intramucosal UD-type EGC that is smaller than 1.0 cm in size. When endoscopically resected specimens show unexpectedly larger tumor size, unexpected submucosal and LVI than that determined at pre-ESD endoscopic diagnosis, an additional gastrectomy with lymphadenectomy should be considered. © 2020 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Keywords: Early gastric cancer Endoscopic submucosal dissection Lymph node metastasis
1. Introduction EGC is considered to be a malignant epithelial lesion of the gastric that is limited to the mucosa or submucosa regardless of the
* Corresponding author. Second Clinical Medical College, Lanzhou University, No. 82 Chuiying Gate, Chengguan District, Lanzhou, 730030, Gansu Province, China. E-mail address: [email protected] (H.-B. Liu). 1 Co-first authors.
presence or absence of LNM.1 Studies showed that the 5-year survival rate of EGC can be as high as 96%.2,3 Endoscopic submucosal dissection (ESD) is minimally invasive therapy for treating EGC that have a negligible risk of LNM.4e6 Because the risk of LNM is negligible, ESD is often used for well or moderately differentiated EGC confined to the mucosa without ulceration and less than or equal to 2.0 cm. UD-type EGC that include mucinous adenocarcinoma, signet ring cell carcinoma and poorly differentiated adenocarcinoma are associated with higher
https://doi.org/10.1016/j.asjsur.2019.12.002 1015-9584/© 2020 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: Liang X-Q et al., Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.12.002
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risk of LMN,1 so the usage of ESD has been limited. However, the indications of ESD has expanded to UD-type early gastric cancer. One of the vital factors in choosing ESD for EGC would be the precise prediction of whether the patients have LNM or not. Previous studies have verified the factors that can help to predict LNM in UD-type EGC. However, few reports have focus on exploration whether ESD can be applied in UD-type EGC. Thus, we would like to determine the validity of the indication of ESD in UD-type EGC. In this study, we retrospectively analyzed the clinicopathological data of patients with UD-type EGC who received radical resection and lymph node dissection in a multiple center. Our results provide a basis for clinical development of reasonable treatment plans. 2. Methods 2.1. Patients This study was a multicenter retrospective trial carried out in 3 hospitals in China. The study selected 203 patients who underwent radical gastrectomy with lymph node dissection for primary gastric adenocarcinoma at multiple medical centers (Gansu Provincial Hospital, Gansu Provincial Cancer Hospital and the 940th of Joint Logistics Support Force of the Chinese People's Liberation Army) between January 2012 and December 2017. Their basic date included age, gender and treatment outcomes were obtained through medical chart reviews and telephone interviews. For this study, inclusion criteria included: (1) patients aged >20 years with UD-type EGC, (2) All patients who underwent D1 or more radical lymphadenectomy, (3) All patients without neoadjuvant radiotherapy, chemotherapy, or chemoradiotherapy, and (4) Available medical record from database. Enrolled patients were divided into 2 groups according to their LNM status: patients with no LNM were assigned to the LNM negative group, and patients with LNM were assigned to the LNM positive group. 2.2. Histopathologic evaluation Histopathological data, including macroscopic type, tumor location, tumor size, tumor depth, LNM, lymphatic vessel involvement (LVI), and perineural invasion, were collected after reviewing histology slides and pathology reports. In histologic review, macroscopic types were classified into 5 types: 0-I (protruding), 0IIa (superficial elevated), 0-IIb (superficial flat), 0-IIc (superficial depressed), and 0-III (excavated).1 We reclassified follows to simplify the evaluation in the present study: 0-I or/and 0-IIa, elevated type; 0-IIb, flat type; 0-IIc or/and 0-III, depressed type. The tumor locations were classified according to the trisected portions of the stomach: upper, middle, and lower parts.1 Tumor size was classified into two groups: < 2.0 cm and 2.0 cm, and poorly differentiated adenocarcinoma, mucinous adenocarcinoma or signet ring cell carcinoma were classified as UD-type. D2-40 and CD31 immunostaining were used as a method to assess the lymphatic vessel involvement (LVI), and perineural involvement (PI) was detected by immunohistochemistry with S-100. All histologic slides of tumor and metastatic were reviewed by two expert pathologists. 2.3. Statistical analysis All statistical analyses were performed using IBM SPSS 20.0 (IBM Corp, Armonk, NY, United States). Continuous variables were reported as mean ± standard deviation (SD), and categorical variables were presented as percentages. Univariable analysis of EGC was performed using Student t test and x2 test analyses to evaluate the association between covariates and lymph node involvement.
Logistic regression model was tests multivariable analysis for risk factors of LNM in EGC. The concordance rate between the biopsy and resected specimens was compared using a percentage. Confidence interval (CI) of 95% and a P value < 0.05 was considered to have statistical significance. 3. Results 3.1. Analysis cohort From 2012 to 2017, a total of 5687 patients with gastric cancer were treated in three centers, including 5090 cases advanced gastric cancer and 597 cases early gastric cancer. Among these EGC, 227 patients with undifferentiated EGC underwent gastrectomy with lymphadenectomy because of early gastric adenocarcinoma. Twenty-four patients were excluded, 16 because they had fewer than 15 LNs in the resected specimen, and 2 because less than 19 years old, and 4 because they had incomplete data in their medical records, and 2 because they had accepted neoadjuvant chemotherapy. Two hundred three patients were eligible to study (40 LNM-positive and 163 LNM-negative). LNM was observed in 19.7%. Of the 203 patients analyzed, the mean age was 54 years (range 22e84 years), 121 (59.6%) were female, the median tumor size was 2.1 cm, 84 (41.4%) were location in lower, 107 (51.71%) were flat, and 111 (54.7%) were in depth submucosal. With regard to the histological type, poorly differentiated accounted for 94.1% (n ¼ 191). The clinicopathologic characteristics are shown in Table 1. 3.2. Risk factors for LNM in UD-type EGC Of the 203 patients with UD-type EGC, 40 (19.7%) were found to have LNM, and that was 7.6% (7/92) and 29.7% (33/111) in intramucosal and submucosal respectively (Fig. 1). Univariable analysis results demonstrated that LNM had a significant correlation with larger tumor size (2.0 cm), submucosal invasion, and LVI (P < 0.05, Table 2), when compared with patients with negative LNM. In contrast, there were no significant differences between LNM and age, sex, tumor location, macroscopic type, location, number of tumor. Multivariable analysis revealed that for LNM, independent
Table 1 Characteristics of 203 patients include in the study. factor
value
Age, years, median (range) Sex (male/female) Tumor size, cm, median (range) Location, n (%) Upper Middle Lower Number of tumor Single Multiple Macroscopic type Elevated Flat Depressed Histology type Poorly differentiated Signet ring cell carcinoma Mucinous adenocarcinoma Depth of invasion Mucosa Submucosa Lymph node metastasis Lymphovascular invasion Perineural invasion
54 (22e84) 121/82 2.1 (0.2e6) 49 (24.1) 70 (34.5) 84 (41.4) 198 (97.5) 5 (2.5) 16 (7.9) 107 (51.7) 80 (40.4) 191 (94.1) 10 (4.9) 2 (1.0) 92 (45.3) 111 (54.7) 40 (19.7) 26 (12.8) 16 (7.9)
Please cite this article as: Liang X-Q et al., Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.12.002
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Table 3 Multivariable analysis of risk factors for lymph node metastasis in UD-type EGC. Characteris
Hazard ratio
95%CI
P-value
Tumor size <2.0 cm 2.0 cm Invasion depth Mucosa Submucosa Lymphovascular invasion Negative Positive
0.368
0.159e0.853
0.020
0.200
0.079e0.506
0.001
0.138
0.053e0.357
<0.001
Table 4 Association between the three identified risk factors and lymph node metastasis in UD-type EGC.
Fig. 1. UD-type EGC with LNM. Among 40 patients in the LNM (þ) group, 11 patients had tumors small 2.0 cm, 12 patients had tumors between 2.0 cm and 3.0 cm, and 17 patients had tumors of 3.0 cm or large.
Table 2 Univariable analysis of risk factors for lymph node metastasis in UD-type EGC. Factors
LN () (n ¼ 163)
LN (þ) (n ¼ 40)
P-value
Age, yrs Sex, n (%) M F Tumor size, cm <2.0 2.0 Location Upper Middle Lower Macroscopic type Elevated Flat Depressed Number of tumors Single Multitude Histology type Poorly differentiated Signet ring cell carcinoma Mucinous adenocarcinoma Depth of invasion Mucosa Submucosa Lymphovascular invasion Negative Positive Perineural invasion Negative Positive
54.9 ± 11.2
51.6 ± 11.8
0.099
100 (82.6) 63 (76.8)
21 (17.4) 19 (23.2)
0.307
98 (95.1) 65 (64.4)
5 (4.9) 35 (35.6)
<0.001
20 (80.0%) 87 (84.5%) 56 (74.7%)
5 (20.0%) 16 (15.5%) 19 (25.3%)
0.268
16 (100.0%) 87 (81.3%) 60 (75.0%)
0 (0.0%) 20 (18.7%) 20 (25.0%)
0.067
161 (81.3) 2 (40.0)
37 (18.7) 3 (60.0)
0.053
83 (78.3) 60 (77.9) 10 (100.0%)
23 (21.7) 17 (22.1) 0 (0.0%)
0.251
85 (92.4) 78 (70.3)
7 (7.6) 33 (29.7)
<0.001
152 (85.9) 11 (42.3)
25 (14.1) 15 (57.7)
<0.001
153 (86.5) 10 (81.2)
34 (13.5) 6 (18.8)
0.124
Number of positive risk factors
Lymph metastasis rate
c2
P-value
None One Two Three
5.1 (2/39) 7.7 (7/91) 37.7 (23/61) 66.7 (8/12)
42.756
<0.001
had tumors less than 1.0 cm, 29 patients had tumors between 1.0 and 2.0 cm, and 51 patients had tumors larger than 2.0 cm. In terms of tumor LNM, 7 (7.6%) patients were associated with regional lymph node metastases. LNM was not observed in patients with smaller than 1.0 cm without LVI. LNM rate was observed in 7.1% (2/ 28) of patients with 1.0 cme2.0 cm. Among patients, one of patients with LNM had tumor 1.0 cm in size (Fig. 2). LNM rate was 50% in patients with 1.0 cme2.0 cm in size with LVI. When tumor size is larger than 2.0 cm, LNM was up to 60% in patients with LVI (Table 5). 3.4. Comparison of histologic type between endoscopic biopsy and resected specimens All 203 patients were diagnosed by both biopsy and resected specimens. 203 patients diagnosed with the undifferentiated cancer postoperatively, 3.9% (8/203) were found to have differentiated cancer preoperatively, and the consistent rate of histologic was 96.1%. 4. Discussion
and significant predictive factors were tumor size 2.0 cm, submucosal invasion, and the presence of LVI (P < 0.05, Table 3). LNM was observed in 5.1% (2/39) of patients who had neither of the three risk factors, whereas, patients with one or two risk factors, LNM were 7.7% (7/91) and 37.7% (23/61) respectively, and the rate of LNM was up to be 66.7% in patients who had three predictive factors (Table 4).
3.3. Intramucosal gastric cancer with LNM Of 92 patients diagnosed with intramucosal EGC, 12 patients
With widespread use of screening esophagogastroduodenoscopy, the proportion of patients diagnosed with EGC is gradually increasing,7e9 which in turn leads to an improvement of prognosis, an increased attention has been focused on the improvement of the quality of life and minimization of invasive surgery. Compared with surgical management, endoscopic approaches, such as endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR), have the benefits of lower procedural risks, shorter postoperative hospital stays, reduced overall postoperative morbidity and fewer complications, including wound dehiscence, anastomotic structuring and bowel obstruction.10,11 The 2019 National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of EMR/ESD for EGC that meet the following criteria: 2.0 cm in diameter, well or moderately well differentiated, negative margins, limited to the superficial submucosa and lacking lymphovascular invasion.12 For patients with UD-type EGC has been ruled out with EMR/ESD due to the risk of LNM. However, Gotoda et al reported that some patients with poorly differentiated showed no LNM after gastrectomy with careful lymph node dissection through reviewing date from a large number of patients, the indication of ESD was expanded to UD-type
Please cite this article as: Liang X-Q et al., Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.12.002
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Fig. 2. Hematoxylin and eosin (H&E) and immunohistochemical staining in the UD-type EGC. A. Diffusely infiltration of tumor cells in the mucosal of gastric (400 , H&E) (B) Tumor thrombus in the vessel (200 , H&E) (C) The strong immunoreactivity of D2-40 with membrane staining pattern in the lymph vessel (400 , IHC) (D) Lymph node metastasis of UD-type EGC cells (400 , H&E).
Table 5 Lymph node metastasis in undifferentiated intramucosal EGC. lymph node metastasis by tumor size in all undifferentiated intramucosal EGC Tumor size
LNM rate (%)
<1.0 cm 1.0e2.0 cm >2.0 cm Total
0.0 7.3 7.8 7.6
(0/12) (3/29) (4/51) (7/92)
lymph node metastasis by tumor size and LVI in undifferentiated intramucosal EGC Tumor size
LNM rate (%); LVI (þ)
LNM rate (%); LVI ()
<1.0 cm 1.0e2.0 cm >2.0 cm Total
0.0 (0/0) 50.0 (1/2) 60.0 (3/5) 57.1 (4/7)
0.0 7.4 2.2 3.5
(0/11) (2/27) (1/46) (3/85)
LVI, lymphatic-vascular involvement; EGC, early gastric cancer; LNM, Lymph node metastasis.
mucosal cancer less than 2.0 cm without ulceration.13 The presence of LNM is the most important prognostic factor in EGC and the vital risk factors in choosing ESD. Although several previous studies verified the risk factors that can help to predict LNM in EGC,14e16 few study have concerned about the applicability of ESD for UD-type EGC. Thus, we sought a possible way to assess the accuracy of clinical in ESD for UD-type EGC by retrospectively study. In the present study, the univariable and multivariable analysis showed that LNM in patients with UD-type EGC has significant risk factors, including tumor larger than 2.0 cm, submucosal invasion, and presence of LVI. Our results are in accordance with previous reports on UD-type EGC, which indicated the existence of a significant correlation between the high incidence of LNM and large tumor size, submucosal invasion and presence of LVI.17e19 We then examined the relationship between the positive
number of the three significant predictive factors (tumor large than 2.0 cm, submucosal invasion, and presence of LVI) and the LNM rate in order to establish management strategies for treatment of UDtype EGC. Our result showed that LNM rates were respectively 7.7%, 37.7% and 66.7% when the number of factors is one, two or three. Therefore radical gastrectomy with regional lymphadenectomy is probably better for such patients with risk factors. Even if patients without any of three factors, we found that LNM rate was 5.1%, which is not consistent with previous studies.18 It's mean that ESD is not acceptable as a curative treatment for these patients. In this study, when compare with intramucosal UD-type EGC, LNM was observed in 29.7% of the submucosal UD-type EGC, it was higher than intramucosal EGC. Thus, ESD should not be considered in case of patients with submucosal UD-type EGC, because of the high probability of LNM and tumor residual. Our result revealed that no LNM was observed in patients with smaller than 1.0 cm without LVI. This may indicated that ESD could alone treat these cases, and that additional surgery is avoided. In contrast, patients with LVI and size between 1.0 cm and 2.0 cm had risk of 10% (3/30) of LNM in intramucosal cancer. That is higher than previous reports,18,20,21 and this result may be caused because our sample size was relatively small. Moreover, intramucosal cancer may have shrunk during process of formalin-fixation and the recorded size in our study may be smaller than the pretreatment size of tumor. If these patients received ESD for treatment, it would be deprived the possibility to be cured by surgery from the patients. When ESD resected specimens show LVI or tumor larger (1.0 cm) than that was diagnosed by pre-ESD endoscopic and an additional surgical procedure should also be considered. Standard gastrectomy with lymphadenectomy is usually indicated for such patients. Laparoscopic lymph node dissection (LLND) may be alternative after ESD, and it could avoid gastrectomy. ESD combined with LLND has a significantly greater effect on overall survival during the long-term follow-up period for EGC patients having a potential risk of LNM.22 When histological examination shows lymph node metastasis after
Please cite this article as: Liang X-Q et al., Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.12.002
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LLND, conventional gastrectomy combined with extended lymphadenectomy should be suggested. Moreover, our result showed that 7.7% of the intramucosal UD-type EGC patients who satisfied the expanded indication of ESD showed LN metastasis. It's mean that ESD for intramucosal undifferentiated cancer has risk of 7.7% of regional lymph node recurrence. Histologic diagnosis using endoscopic biopsy specimens is presently the criterion standard for EGC diagnosis and histologic typing. However, several studies showed a 7.7%e25% discrepancy rate in undifferentiated EGC determined by biopsy and resected specimens, and these histologic type discrepancies was related to risk factors, such as tumor size, tumor location, and the heterogeneity of gastric cancer.23e25 In the current study, discrepancy rate was approximately 3.9%. Such discrepancies may result in actual UD-type patients to miss opportunities for curative radical treatment while causing actual UD-type cancer patients undergoing unnecessary surgery. In addition to, the specimen resected by ESD would be carefully estimated, because all of the predictive factors, particularly LVI, become first evident. Accurate histological examination decided whether the additional surgery was needed. However, our study had some limitation. First, although most patients received D1 or D1þ lymphadenectomy, this study was not a randomized controlled study and the extent of lymphadenectomy was not consistent in all patients. Therefore, LNM could have been underestimated in some patients, leading to a selection bias. Moreover, our sample size was relatively small. Therefore, our findings and conclusions may not provide sufficient information to draw strong conclusions. We intend to conduct a prospective trial to investigate these results. 5. Conclusions In conclusion, this study demonstrated that a tumor larger than 2.0 cm, submucosal invasion, and the presence of LVI was independently associated with the presence of LNM in UD-type EGC. Intramucosal UD-type EGC that is less than 1.0 cm in diameter without lymphatic involvement may be considered suitable for ESD due to the negligible risk of lymph node metastasis. If patients show with LVI, submucosal invasion, and larger tumor size than that determined at pre-ESD endoscopic diagnosis, an additional radical gastrectomy is probably better for these patients. Author contribution Liu HB designed this study. Liang XQ and Wang Z contributed equally to this work. Liang XQ, Wang Z, Zhou HC and Gui M were involved in acquisition of data, analysis. Liang XQ and Wang Z interpreted the results and drafted the article; Li HT and WeneWen Yu revised the paper. All authors are in agreement with the content of the manuscript. Funding This work was supported by Natural Science Foundations Project of Gansu Province (18JR3RA050). Declaration of competing interest
5
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All authors declare no conflicts of interest related to this article.
Please cite this article as: Liang X-Q et al., Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.12.002
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Asian Journal of Surgery journal homepage: www.e-asianjournalsurgery.com
Original Article
Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer Xiao-Qin Liang a, b, 1, Zhuo Wang b, 1, Hong-Tao Li c, 1, Gui Ma d, Wen-Wen Yu a, Hai-Cun Zhou a, Hong-Bin Liu a, c, * a
Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, Gansu Province, China Department of Pathology, Gansu Province People's Hospital, Lanzhou, 730000, Gansu Province, China Department of General Surgery, The 940th of Joint Logistics Support Force of the Chinese People's Liberation Army, Lanzhou, 730050, Gansu Province, China d Department of Pathology, Gansu Provincial Cancer Hospital, Lanzhou, 730050, Gansu Province, China b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 July 2019 Received in revised form 30 October 2019 Accepted 8 December 2019 Available online xxx
Background: Despite the risk of lymph node metastasis (LNM), the indications of endoscopic submucosal dissection (ESD) has expanded to undifferentiated type (UD-type) early gastric cancer (EGC). There is debate as to whether the endoscopic resection can be used. This study was conducted to evaluate risk factors for LNM in undifferentiated early gastric cancer, implications for the indication of the ESD so as to providing evidence for proper clinical management for UD-type EGC. Method: We retrospectively analyzed 203 patients with UD-type EGC who underwent gastrectomy for primary gastric adenocarcinoma between 2012 and 2017. We evaluated the relationship between the clinicopathological factors and the presence of LNM using univariable and multivariable logistic regression analyses. Results: A total of 203 UD-type EGC patients were enrolled, and LNM was positive in 40 cases (19.7%). Multivariable logistic regression analysis identified three independent risk factors for LNM, the tumor size (2.0 cm, P < 0.001), depth of invasion (P < 0.001), and lymphatic vessel involvement (LVI, P < 0.001). LNM was observed in 5.9% patients without the three predictive factors in UD-type EGC, whereas 7.7% and 37.7% of patients with one and two risk factors had LNM, respectively. In contrast, the LNM rate was up to be 66.7% in patients with three factors. Of 41 patients satisfying the expanded indication of ESD, 3 patients (7.3%) showed LNM. LNM was not found in any of 12 patients with small intramucosal lesions (<1.0 cm) without LVI. Conclusions: LNM-related risk factors were tumor larger than 2.0 cm, submucosal invasion, and the presence of LVI in UD-type EGC. ESD alone may be sufficient treatment for the intramucosal UD-type EGC that is smaller than 1.0 cm in size. When endoscopically resected specimens show unexpectedly larger tumor size, unexpected submucosal and LVI than that determined at pre-ESD endoscopic diagnosis, an additional gastrectomy with lymphadenectomy should be considered. © 2020 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).
Keywords: Early gastric cancer Endoscopic submucosal dissection Lymph node metastasis
1. Introduction EGC is considered to be a malignant epithelial lesion of the gastric that is limited to the mucosa or submucosa regardless of the
* Corresponding author. Second Clinical Medical College, Lanzhou University, No. 82 Chuiying Gate, Chengguan District, Lanzhou, 730030, Gansu Province, China. E-mail address: [email protected] (H.-B. Liu). 1 Co-first authors.
presence or absence of LNM.1 Studies showed that the 5-year survival rate of EGC can be as high as 96%.2,3 Endoscopic submucosal dissection (ESD) is minimally invasive therapy for treating EGC that have a negligible risk of LNM.4e6 Because the risk of LNM is negligible, ESD is often used for well or moderately differentiated EGC confined to the mucosa without ulceration and less than or equal to 2.0 cm. UD-type EGC that include mucinous adenocarcinoma, signet ring cell carcinoma and poorly differentiated adenocarcinoma are associated with higher
https://doi.org/10.1016/j.asjsur.2019.12.002 1015-9584/© 2020 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NCND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article as: Liang X-Q et al., Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.12.002
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risk of LMN,1 so the usage of ESD has been limited. However, the indications of ESD has expanded to UD-type early gastric cancer. One of the vital factors in choosing ESD for EGC would be the precise prediction of whether the patients have LNM or not. Previous studies have verified the factors that can help to predict LNM in UD-type EGC. However, few reports have focus on exploration whether ESD can be applied in UD-type EGC. Thus, we would like to determine the validity of the indication of ESD in UD-type EGC. In this study, we retrospectively analyzed the clinicopathological data of patients with UD-type EGC who received radical resection and lymph node dissection in a multiple center. Our results provide a basis for clinical development of reasonable treatment plans. 2. Methods 2.1. Patients This study was a multicenter retrospective trial carried out in 3 hospitals in China. The study selected 203 patients who underwent radical gastrectomy with lymph node dissection for primary gastric adenocarcinoma at multiple medical centers (Gansu Provincial Hospital, Gansu Provincial Cancer Hospital and the 940th of Joint Logistics Support Force of the Chinese People's Liberation Army) between January 2012 and December 2017. Their basic date included age, gender and treatment outcomes were obtained through medical chart reviews and telephone interviews. For this study, inclusion criteria included: (1) patients aged >20 years with UD-type EGC, (2) All patients who underwent D1 or more radical lymphadenectomy, (3) All patients without neoadjuvant radiotherapy, chemotherapy, or chemoradiotherapy, and (4) Available medical record from database. Enrolled patients were divided into 2 groups according to their LNM status: patients with no LNM were assigned to the LNM negative group, and patients with LNM were assigned to the LNM positive group. 2.2. Histopathologic evaluation Histopathological data, including macroscopic type, tumor location, tumor size, tumor depth, LNM, lymphatic vessel involvement (LVI), and perineural invasion, were collected after reviewing histology slides and pathology reports. In histologic review, macroscopic types were classified into 5 types: 0-I (protruding), 0IIa (superficial elevated), 0-IIb (superficial flat), 0-IIc (superficial depressed), and 0-III (excavated).1 We reclassified follows to simplify the evaluation in the present study: 0-I or/and 0-IIa, elevated type; 0-IIb, flat type; 0-IIc or/and 0-III, depressed type. The tumor locations were classified according to the trisected portions of the stomach: upper, middle, and lower parts.1 Tumor size was classified into two groups: < 2.0 cm and 2.0 cm, and poorly differentiated adenocarcinoma, mucinous adenocarcinoma or signet ring cell carcinoma were classified as UD-type. D2-40 and CD31 immunostaining were used as a method to assess the lymphatic vessel involvement (LVI), and perineural involvement (PI) was detected by immunohistochemistry with S-100. All histologic slides of tumor and metastatic were reviewed by two expert pathologists. 2.3. Statistical analysis All statistical analyses were performed using IBM SPSS 20.0 (IBM Corp, Armonk, NY, United States). Continuous variables were reported as mean ± standard deviation (SD), and categorical variables were presented as percentages. Univariable analysis of EGC was performed using Student t test and x2 test analyses to evaluate the association between covariates and lymph node involvement.
Logistic regression model was tests multivariable analysis for risk factors of LNM in EGC. The concordance rate between the biopsy and resected specimens was compared using a percentage. Confidence interval (CI) of 95% and a P value < 0.05 was considered to have statistical significance. 3. Results 3.1. Analysis cohort From 2012 to 2017, a total of 5687 patients with gastric cancer were treated in three centers, including 5090 cases advanced gastric cancer and 597 cases early gastric cancer. Among these EGC, 227 patients with undifferentiated EGC underwent gastrectomy with lymphadenectomy because of early gastric adenocarcinoma. Twenty-four patients were excluded, 16 because they had fewer than 15 LNs in the resected specimen, and 2 because less than 19 years old, and 4 because they had incomplete data in their medical records, and 2 because they had accepted neoadjuvant chemotherapy. Two hundred three patients were eligible to study (40 LNM-positive and 163 LNM-negative). LNM was observed in 19.7%. Of the 203 patients analyzed, the mean age was 54 years (range 22e84 years), 121 (59.6%) were female, the median tumor size was 2.1 cm, 84 (41.4%) were location in lower, 107 (51.71%) were flat, and 111 (54.7%) were in depth submucosal. With regard to the histological type, poorly differentiated accounted for 94.1% (n ¼ 191). The clinicopathologic characteristics are shown in Table 1. 3.2. Risk factors for LNM in UD-type EGC Of the 203 patients with UD-type EGC, 40 (19.7%) were found to have LNM, and that was 7.6% (7/92) and 29.7% (33/111) in intramucosal and submucosal respectively (Fig. 1). Univariable analysis results demonstrated that LNM had a significant correlation with larger tumor size (2.0 cm), submucosal invasion, and LVI (P < 0.05, Table 2), when compared with patients with negative LNM. In contrast, there were no significant differences between LNM and age, sex, tumor location, macroscopic type, location, number of tumor. Multivariable analysis revealed that for LNM, independent
Table 1 Characteristics of 203 patients include in the study. factor
value
Age, years, median (range) Sex (male/female) Tumor size, cm, median (range) Location, n (%) Upper Middle Lower Number of tumor Single Multiple Macroscopic type Elevated Flat Depressed Histology type Poorly differentiated Signet ring cell carcinoma Mucinous adenocarcinoma Depth of invasion Mucosa Submucosa Lymph node metastasis Lymphovascular invasion Perineural invasion
54 (22e84) 121/82 2.1 (0.2e6) 49 (24.1) 70 (34.5) 84 (41.4) 198 (97.5) 5 (2.5) 16 (7.9) 107 (51.7) 80 (40.4) 191 (94.1) 10 (4.9) 2 (1.0) 92 (45.3) 111 (54.7) 40 (19.7) 26 (12.8) 16 (7.9)
Please cite this article as: Liang X-Q et al., Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.12.002
X.-Q. Liang et al. / Asian Journal of Surgery xxx (xxxx) xxx
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Table 3 Multivariable analysis of risk factors for lymph node metastasis in UD-type EGC. Characteris
Hazard ratio
95%CI
P-value
Tumor size <2.0 cm 2.0 cm Invasion depth Mucosa Submucosa Lymphovascular invasion Negative Positive
0.368
0.159e0.853
0.020
0.200
0.079e0.506
0.001
0.138
0.053e0.357
<0.001
Table 4 Association between the three identified risk factors and lymph node metastasis in UD-type EGC.
Fig. 1. UD-type EGC with LNM. Among 40 patients in the LNM (þ) group, 11 patients had tumors small 2.0 cm, 12 patients had tumors between 2.0 cm and 3.0 cm, and 17 patients had tumors of 3.0 cm or large.
Table 2 Univariable analysis of risk factors for lymph node metastasis in UD-type EGC. Factors
LN () (n ¼ 163)
LN (þ) (n ¼ 40)
P-value
Age, yrs Sex, n (%) M F Tumor size, cm <2.0 2.0 Location Upper Middle Lower Macroscopic type Elevated Flat Depressed Number of tumors Single Multitude Histology type Poorly differentiated Signet ring cell carcinoma Mucinous adenocarcinoma Depth of invasion Mucosa Submucosa Lymphovascular invasion Negative Positive Perineural invasion Negative Positive
54.9 ± 11.2
51.6 ± 11.8
0.099
100 (82.6) 63 (76.8)
21 (17.4) 19 (23.2)
0.307
98 (95.1) 65 (64.4)
5 (4.9) 35 (35.6)
<0.001
20 (80.0%) 87 (84.5%) 56 (74.7%)
5 (20.0%) 16 (15.5%) 19 (25.3%)
0.268
16 (100.0%) 87 (81.3%) 60 (75.0%)
0 (0.0%) 20 (18.7%) 20 (25.0%)
0.067
161 (81.3) 2 (40.0)
37 (18.7) 3 (60.0)
0.053
83 (78.3) 60 (77.9) 10 (100.0%)
23 (21.7) 17 (22.1) 0 (0.0%)
0.251
85 (92.4) 78 (70.3)
7 (7.6) 33 (29.7)
<0.001
152 (85.9) 11 (42.3)
25 (14.1) 15 (57.7)
<0.001
153 (86.5) 10 (81.2)
34 (13.5) 6 (18.8)
0.124
Number of positive risk factors
Lymph metastasis rate
c2
P-value
None One Two Three
5.1 (2/39) 7.7 (7/91) 37.7 (23/61) 66.7 (8/12)
42.756
<0.001
had tumors less than 1.0 cm, 29 patients had tumors between 1.0 and 2.0 cm, and 51 patients had tumors larger than 2.0 cm. In terms of tumor LNM, 7 (7.6%) patients were associated with regional lymph node metastases. LNM was not observed in patients with smaller than 1.0 cm without LVI. LNM rate was observed in 7.1% (2/ 28) of patients with 1.0 cme2.0 cm. Among patients, one of patients with LNM had tumor 1.0 cm in size (Fig. 2). LNM rate was 50% in patients with 1.0 cme2.0 cm in size with LVI. When tumor size is larger than 2.0 cm, LNM was up to 60% in patients with LVI (Table 5). 3.4. Comparison of histologic type between endoscopic biopsy and resected specimens All 203 patients were diagnosed by both biopsy and resected specimens. 203 patients diagnosed with the undifferentiated cancer postoperatively, 3.9% (8/203) were found to have differentiated cancer preoperatively, and the consistent rate of histologic was 96.1%. 4. Discussion
and significant predictive factors were tumor size 2.0 cm, submucosal invasion, and the presence of LVI (P < 0.05, Table 3). LNM was observed in 5.1% (2/39) of patients who had neither of the three risk factors, whereas, patients with one or two risk factors, LNM were 7.7% (7/91) and 37.7% (23/61) respectively, and the rate of LNM was up to be 66.7% in patients who had three predictive factors (Table 4).
3.3. Intramucosal gastric cancer with LNM Of 92 patients diagnosed with intramucosal EGC, 12 patients
With widespread use of screening esophagogastroduodenoscopy, the proportion of patients diagnosed with EGC is gradually increasing,7e9 which in turn leads to an improvement of prognosis, an increased attention has been focused on the improvement of the quality of life and minimization of invasive surgery. Compared with surgical management, endoscopic approaches, such as endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR), have the benefits of lower procedural risks, shorter postoperative hospital stays, reduced overall postoperative morbidity and fewer complications, including wound dehiscence, anastomotic structuring and bowel obstruction.10,11 The 2019 National Comprehensive Cancer Network (NCCN) guidelines recommend consideration of EMR/ESD for EGC that meet the following criteria: 2.0 cm in diameter, well or moderately well differentiated, negative margins, limited to the superficial submucosa and lacking lymphovascular invasion.12 For patients with UD-type EGC has been ruled out with EMR/ESD due to the risk of LNM. However, Gotoda et al reported that some patients with poorly differentiated showed no LNM after gastrectomy with careful lymph node dissection through reviewing date from a large number of patients, the indication of ESD was expanded to UD-type
Please cite this article as: Liang X-Q et al., Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.12.002
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X.-Q. Liang et al. / Asian Journal of Surgery xxx (xxxx) xxx
Fig. 2. Hematoxylin and eosin (H&E) and immunohistochemical staining in the UD-type EGC. A. Diffusely infiltration of tumor cells in the mucosal of gastric (400 , H&E) (B) Tumor thrombus in the vessel (200 , H&E) (C) The strong immunoreactivity of D2-40 with membrane staining pattern in the lymph vessel (400 , IHC) (D) Lymph node metastasis of UD-type EGC cells (400 , H&E).
Table 5 Lymph node metastasis in undifferentiated intramucosal EGC. lymph node metastasis by tumor size in all undifferentiated intramucosal EGC Tumor size
LNM rate (%)
<1.0 cm 1.0e2.0 cm >2.0 cm Total
0.0 7.3 7.8 7.6
(0/12) (3/29) (4/51) (7/92)
lymph node metastasis by tumor size and LVI in undifferentiated intramucosal EGC Tumor size
LNM rate (%); LVI (þ)
LNM rate (%); LVI ()
<1.0 cm 1.0e2.0 cm >2.0 cm Total
0.0 (0/0) 50.0 (1/2) 60.0 (3/5) 57.1 (4/7)
0.0 7.4 2.2 3.5
(0/11) (2/27) (1/46) (3/85)
LVI, lymphatic-vascular involvement; EGC, early gastric cancer; LNM, Lymph node metastasis.
mucosal cancer less than 2.0 cm without ulceration.13 The presence of LNM is the most important prognostic factor in EGC and the vital risk factors in choosing ESD. Although several previous studies verified the risk factors that can help to predict LNM in EGC,14e16 few study have concerned about the applicability of ESD for UD-type EGC. Thus, we sought a possible way to assess the accuracy of clinical in ESD for UD-type EGC by retrospectively study. In the present study, the univariable and multivariable analysis showed that LNM in patients with UD-type EGC has significant risk factors, including tumor larger than 2.0 cm, submucosal invasion, and presence of LVI. Our results are in accordance with previous reports on UD-type EGC, which indicated the existence of a significant correlation between the high incidence of LNM and large tumor size, submucosal invasion and presence of LVI.17e19 We then examined the relationship between the positive
number of the three significant predictive factors (tumor large than 2.0 cm, submucosal invasion, and presence of LVI) and the LNM rate in order to establish management strategies for treatment of UDtype EGC. Our result showed that LNM rates were respectively 7.7%, 37.7% and 66.7% when the number of factors is one, two or three. Therefore radical gastrectomy with regional lymphadenectomy is probably better for such patients with risk factors. Even if patients without any of three factors, we found that LNM rate was 5.1%, which is not consistent with previous studies.18 It's mean that ESD is not acceptable as a curative treatment for these patients. In this study, when compare with intramucosal UD-type EGC, LNM was observed in 29.7% of the submucosal UD-type EGC, it was higher than intramucosal EGC. Thus, ESD should not be considered in case of patients with submucosal UD-type EGC, because of the high probability of LNM and tumor residual. Our result revealed that no LNM was observed in patients with smaller than 1.0 cm without LVI. This may indicated that ESD could alone treat these cases, and that additional surgery is avoided. In contrast, patients with LVI and size between 1.0 cm and 2.0 cm had risk of 10% (3/30) of LNM in intramucosal cancer. That is higher than previous reports,18,20,21 and this result may be caused because our sample size was relatively small. Moreover, intramucosal cancer may have shrunk during process of formalin-fixation and the recorded size in our study may be smaller than the pretreatment size of tumor. If these patients received ESD for treatment, it would be deprived the possibility to be cured by surgery from the patients. When ESD resected specimens show LVI or tumor larger (1.0 cm) than that was diagnosed by pre-ESD endoscopic and an additional surgical procedure should also be considered. Standard gastrectomy with lymphadenectomy is usually indicated for such patients. Laparoscopic lymph node dissection (LLND) may be alternative after ESD, and it could avoid gastrectomy. ESD combined with LLND has a significantly greater effect on overall survival during the long-term follow-up period for EGC patients having a potential risk of LNM.22 When histological examination shows lymph node metastasis after
Please cite this article as: Liang X-Q et al., Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.12.002
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LLND, conventional gastrectomy combined with extended lymphadenectomy should be suggested. Moreover, our result showed that 7.7% of the intramucosal UD-type EGC patients who satisfied the expanded indication of ESD showed LN metastasis. It's mean that ESD for intramucosal undifferentiated cancer has risk of 7.7% of regional lymph node recurrence. Histologic diagnosis using endoscopic biopsy specimens is presently the criterion standard for EGC diagnosis and histologic typing. However, several studies showed a 7.7%e25% discrepancy rate in undifferentiated EGC determined by biopsy and resected specimens, and these histologic type discrepancies was related to risk factors, such as tumor size, tumor location, and the heterogeneity of gastric cancer.23e25 In the current study, discrepancy rate was approximately 3.9%. Such discrepancies may result in actual UD-type patients to miss opportunities for curative radical treatment while causing actual UD-type cancer patients undergoing unnecessary surgery. In addition to, the specimen resected by ESD would be carefully estimated, because all of the predictive factors, particularly LVI, become first evident. Accurate histological examination decided whether the additional surgery was needed. However, our study had some limitation. First, although most patients received D1 or D1þ lymphadenectomy, this study was not a randomized controlled study and the extent of lymphadenectomy was not consistent in all patients. Therefore, LNM could have been underestimated in some patients, leading to a selection bias. Moreover, our sample size was relatively small. Therefore, our findings and conclusions may not provide sufficient information to draw strong conclusions. We intend to conduct a prospective trial to investigate these results. 5. Conclusions In conclusion, this study demonstrated that a tumor larger than 2.0 cm, submucosal invasion, and the presence of LVI was independently associated with the presence of LNM in UD-type EGC. Intramucosal UD-type EGC that is less than 1.0 cm in diameter without lymphatic involvement may be considered suitable for ESD due to the negligible risk of lymph node metastasis. If patients show with LVI, submucosal invasion, and larger tumor size than that determined at pre-ESD endoscopic diagnosis, an additional radical gastrectomy is probably better for these patients. Author contribution Liu HB designed this study. Liang XQ and Wang Z contributed equally to this work. Liang XQ, Wang Z, Zhou HC and Gui M were involved in acquisition of data, analysis. Liang XQ and Wang Z interpreted the results and drafted the article; Li HT and WeneWen Yu revised the paper. All authors are in agreement with the content of the manuscript. Funding This work was supported by Natural Science Foundations Project of Gansu Province (18JR3RA050). Declaration of competing interest
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All authors declare no conflicts of interest related to this article.
Please cite this article as: Liang X-Q et al., Indication for endoscopic treatment based on the risk of lymph node metastasis in patients with undifferentiated early gastric cancer, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.12.002