TY - JOUR
AU - Kim, B-S
AB - Abstract Background Endoscopic submucosal dissection (ESD) is not considered appropriate for all submucosal cancers owing to the risk of lymph node metastasis and difficulty estimating the deep margin status. This study aimed to determine predictive factors for lymph node metastases in submucosal cancer and to explore in which patients ESD might be feasible. Methods Details of patients who had curative gastrectomy for submucosal gastric cancer at Asan Medical Centre from 2007 to 2011 were reviewed retrospectively to determine the relationship between lymph node metastasis and clinicopathological characteristics, including age, sex, tumour location, size, gross appearance, depth of invasion, histological type/differentiation, presence of lymphovascular/perineural invasion, and immunohistochemical staining results for p53, human epidermal growth factor receptor (HER) 1 and HER2. Results A total of 1773 patients were analysed. The presence of lymphovascular invasion was related most strongly to lymph node metastasis. Multivariable analysis revealed that depth of invasion, tumour size, differentiation, gross appearance and perineural invasion were also related. Metastatic lymph nodes were found in four of 105 patients who met the classical criteria for ESD; all showed a moderately differentiated histological appearance. No lymph node metastases were observed in well differentiated SM1 tumours of any size (infiltration into upper third of submucosa), or in well differentiated SM2 (infiltration into middle third of submucosa) tumours of 2 cm or less without lymphovascular invasion. Conclusion Patients with well differentiated SM1 cancer of any size and those with well differentiated SM2 cancer of 2 cm or less without lymphovascular invasion may be suitable candidates for ESD. Introduction Endoscopic mucosal resection and endoscopic submucosal dissection (ESD) are used widely in the treatment of early gastric cancer with mucosal invasion. Generally accepted indications for endoscopic treatment include well or moderately differentiated intramucosal cancers with a diameter of less than 3 cm and without ulceration1. Recently, several studies have proposed extended criteria for ESD, including well-differentiated mucosal cancer of any size without ulceration, and well-differentiated mucosal cancer of 3 cm or less in size with ulceration2,3. Gotoda and colleagues2 reported that well-differentiated submucosal cancers (SM1, about 500 µm from the muscularis mucosa) smaller than 3 cm in size without lymphovascular invasion were unlikely to have lymph node metastasis and might be eligible for endoscopic resection. Endoscopic treatment may provide better quality of life to patients than radical surgery, but there are several limitations in performing ESD for submucosal gastric cancer compared with mucosal cancer. First, the incidence of lymph node metastasis in submucosal cancer is about 20 per cent4–6. The higher frequency of nodal metastasis compared with that in mucosal cancer is the main reason why ESD is not considered an alternative treatment for submucosal cancer. Second, exact characterization of the deep margin status may be impossible without full-thickness gastric resection. Although some authors have suggested the use of 500 µm from the muscularis mucosa as a criterion for SM1, the clinical value of this has yet to be determined. Finally, few reports have investigated predictors of lymph node metastasis in a subgroup of patients with submucosal cancer only, although there are studies for the whole group of early gastric cancer2,7–9. This study aimed to determine predictive factors related to lymph node metastasis in submucosal gastric cancer, to categorize patients with a low risk of node metastasis, and to explore whether ESD might be suitable in selected patients. Methods This retrospective study adhered to the guidelines established by the Declaration of Helsinki and was approved by the institutional review board of Asan Medical Centre, Seoul, Korea. All patients who underwent curative gastrectomy with extended lymphadenectomy for submucosal gastric cancer at Asan Medical Centre from 2007 to 2011 were identified. During that interval, no patient was recommended to have endoscopic resection and all patients had the standard operation. Medical records were analysed retrospectively to determine clinicopathological characteristics, including age at operation, sex, tumour location, size and gross appearance of the lesion, number of metastatic lymph nodes, depth of invasion, histological type and differentiation by World Health Organization and Laurén classifications, and the presence of lymphovascular or perineural invasion. Results of immunohistochemical staining for p53, human epidermal growth factor receptor (HER) 1 and HER2 were assessed. Patients with tumours in a remnant stomach, those who had neoadjuvant chemotherapy, and those with a synchronous malignancy in another organ were excluded from the study. All specimens were reviewed by experienced gastrointestinal pathologists based on the criteria of the Japanese Gastric Cancer Association10. The depth of submucosal infiltration was classified into three categories: SM1, upper third of submucosa; SM2, middle third; and SM3, lower third. Tumour locations were grouped into the upper, middle and lower third of the stomach. The gross appearance of early gastric cancer was classified according to the Paris endoscopic classification of superficial neoplastic lesions11 as: type I (protruded), IIa (superficial, elevated), IIb (flat), IIc (superficial, depressed) and III (excavated). In addition, tumours were reclassified into three groups: elevated type (I, IIa, IIa + IIb, IIa + IIc), flat type (IIb, IIb + IIa, IIb + IIc) and depressed type (IIc, IIc + IIa, IIc + IIb, IIc + III, III) according to their primary morphology. With regard to differentiation status, a tumour was defined as well differentiated if it had a glandular structure over more than 75 per cent of its area. Moderately and poorly differentiated histological appearance referred to 25–75 and less than 25 per cent glandular structure respectively. Lymphovascular invasion was judged to have occurred when tumour cells were identified in a tubular space lined by endothelial cells or inside a vascular wall structure. Immunohistochemical staining for p53 and HER1 was considered positive if more than 10 per cent of the tumour cells showed positive staining. HER2 staining was categorized into three groups: negative, equivocal and positive. Statistical analysis The statistical software SPSS® version 12.0 for Windows® (IBM, Armonk, New York, USA) was used for all statistical analyses. The χ2 test was used to assess the relation of lymph node metastases with tumour location, size, gross appearance, depth of invasion, differentiation, presence of lymphovascular/perineural invasion and immunohistochemical staining results. Statistical significance was set at P < 0·050. Factors found to be significant in univariable analysis were included in a multivariable logistic regression analysis to investigate the influence of the tested variables. The hazard ratio for lymph node metastases and its 95 per cent confidence interval (c.i.) were estimated for each variable. Results Clinicopathological findings A total of 1773 patients who had gastrectomy and lymphadenectomy with curative intent for submucosal gastric cancer during the study period were identified. Of these, 1199 (67·6 per cent) were men and 574 (32·4 per cent) were women. Median age at operation was 58 (range 26–84) years. A median of 28 (range 3–85) lymph nodes were harvested, and the overall occurrence of lymph node metastasis was 20·5 per cent (364 of 1773). About two-thirds of tumours (65·8 per cent) were located in the lower third of the stomach, and more than half of the lesions (55·3 per cent) had a depressed appearance. Poorly differentiated histology and SM3 layer involvement were observed in more than half of the patients (both 53·1 per cent). Lymphovascular and perineural invasion were found in 24·9 and 9·0 per cent of patients respectively (Table 1). Table 1 Pathological findings in patients with early gastric cancer invading the submucosa . No. of patients* (n = 1773) . Tumour size (cm)† 3·3 (0·3–18·0) No. of harvested lymph nodes 28 (3–85) Gross appearance  Elevated 458 (25·8)  Flat 334 (18·8)  Depressed 981 (55·3) Depth of invasion  SM1 351 (19·8)  SM2 480 (27·1)  SM3 942 (53·1) Differentiation‡  Well differentiated 171 (9·8)  Moderately differentiated 650 (37·1)  Poorly differentiated 931 (53·1) Lymphovascular invasion  Yes 442 (24·9)  No 1331 (75·1) Perineural invasion  Yes 160 (9·0)  No 1613 (91·0) . No. of patients* (n = 1773) . Tumour size (cm)† 3·3 (0·3–18·0) No. of harvested lymph nodes 28 (3–85) Gross appearance  Elevated 458 (25·8)  Flat 334 (18·8)  Depressed 981 (55·3) Depth of invasion  SM1 351 (19·8)  SM2 480 (27·1)  SM3 942 (53·1) Differentiation‡  Well differentiated 171 (9·8)  Moderately differentiated 650 (37·1)  Poorly differentiated 931 (53·1) Lymphovascular invasion  Yes 442 (24·9)  No 1331 (75·1) Perineural invasion  Yes 160 (9·0)  No 1613 (91·0) * Unless indicated otherwise; † values are median (range). SM1, infiltration into upper third of submucosa SM2, infiltration into middle third of submucosa SM3, infiltration into lower third of submucosa ‡ Some data were absent from pathology reports. Open in new tab Table 1 Pathological findings in patients with early gastric cancer invading the submucosa . No. of patients* (n = 1773) . Tumour size (cm)† 3·3 (0·3–18·0) No. of harvested lymph nodes 28 (3–85) Gross appearance  Elevated 458 (25·8)  Flat 334 (18·8)  Depressed 981 (55·3) Depth of invasion  SM1 351 (19·8)  SM2 480 (27·1)  SM3 942 (53·1) Differentiation‡  Well differentiated 171 (9·8)  Moderately differentiated 650 (37·1)  Poorly differentiated 931 (53·1) Lymphovascular invasion  Yes 442 (24·9)  No 1331 (75·1) Perineural invasion  Yes 160 (9·0)  No 1613 (91·0) . No. of patients* (n = 1773) . Tumour size (cm)† 3·3 (0·3–18·0) No. of harvested lymph nodes 28 (3–85) Gross appearance  Elevated 458 (25·8)  Flat 334 (18·8)  Depressed 981 (55·3) Depth of invasion  SM1 351 (19·8)  SM2 480 (27·1)  SM3 942 (53·1) Differentiation‡  Well differentiated 171 (9·8)  Moderately differentiated 650 (37·1)  Poorly differentiated 931 (53·1) Lymphovascular invasion  Yes 442 (24·9)  No 1331 (75·1) Perineural invasion  Yes 160 (9·0)  No 1613 (91·0) * Unless indicated otherwise; † values are median (range). SM1, infiltration into upper third of submucosa SM2, infiltration into middle third of submucosa SM3, infiltration into lower third of submucosa ‡ Some data were absent from pathology reports. Open in new tab Predictive factors for lymph node metastasis Lymphovascular invasion, depth of invasion, tumour size, gross appearance, differentiation and perineural invasion were significantly associated with lymph node metastasis in submucosal gastric cancer in both univariable and multivariable analyses (Tables 2 and 3). The presence of lymphovascular invasion was the most powerful predictor of lymph node metastasis (P < 0·001), followed by depth of invasion (P < 0·001) and tumour size (P < 0·001). Metastatic lymph nodes were seen in 46·6 per cent of tumours with lymphovascular involvement. The proportion of patients with metastatic nodes in tumours invading the SM1, SM2 and SM3 layers was 8·5, 14·2 and 28·2 per cent respectively. Larger tumours had an increased risk of lymph node involvement. Tumours with an elevated morphology were more often associated with lymph node metastasis than those with a flat or depressed type (P < 0·001). With regard to differentiation, the Laurén classification and categorization by differentiated/undifferentiated type were significant in multivariable analysis (P = 0·022 and P = 0·027 respectively). Further, classification into well/moderately/poorly differentiated histology was highly significant (P = 0·008). Table 2 Univariable analysis of predictive factors for lymph node metastasis in 1773 patients with early gastric cancer invading the submucosa . Lymph node metastasis . . Negative . Positive . P* . Lymphovascular invasion < 0·001  Present 236 (53·4) 206 (46·6)  Absent 1173 (88·1) 158 (11·9) Depth of invasion < 0·001  SM1 321 (91·5) 30 (8·5)  SM2 412 (85·8) 68 (14·2)  SM3 676 (71·8) 266 (28·2) Tumour size (cm) < 0·001  < 1 36 (88) 5 (12)  1–2 297 (89·7) 34 (10·3)  2–3 376 (83·9) 72 (16·1)  > 3 700 (73·5) 253 (26·5) Gross appearance < 0·001  Elevated 325 (70·9) 133 (29·1)  Flat 281 (84·1) 53 (15·9)  Depressed 803 (81·9) 178 (18·1) Differentiation 0·003  Well differentiated 153 (89·5) 18 (10·5)  Moderately differentiated 521 (80·2) 129 (19·8)  Poorly differentiated 723 (77·7) 208 (22·3) Perineural invasion < 0·001  Yes 113 (70·6) 47 (29·4)  No 1296 (80·3) 317 (19·7) . Lymph node metastasis . . Negative . Positive . P* . Lymphovascular invasion < 0·001  Present 236 (53·4) 206 (46·6)  Absent 1173 (88·1) 158 (11·9) Depth of invasion < 0·001  SM1 321 (91·5) 30 (8·5)  SM2 412 (85·8) 68 (14·2)  SM3 676 (71·8) 266 (28·2) Tumour size (cm) < 0·001  < 1 36 (88) 5 (12)  1–2 297 (89·7) 34 (10·3)  2–3 376 (83·9) 72 (16·1)  > 3 700 (73·5) 253 (26·5) Gross appearance < 0·001  Elevated 325 (70·9) 133 (29·1)  Flat 281 (84·1) 53 (15·9)  Depressed 803 (81·9) 178 (18·1) Differentiation 0·003  Well differentiated 153 (89·5) 18 (10·5)  Moderately differentiated 521 (80·2) 129 (19·8)  Poorly differentiated 723 (77·7) 208 (22·3) Perineural invasion < 0·001  Yes 113 (70·6) 47 (29·4)  No 1296 (80·3) 317 (19·7) Values in parentheses are percentages. SM1, infiltration into upper third of submucosa SM2, infiltration into middle third of submucosa SM3, infiltration into lower third of submucosa. * χ2 test. Open in new tab Table 2 Univariable analysis of predictive factors for lymph node metastasis in 1773 patients with early gastric cancer invading the submucosa . Lymph node metastasis . . Negative . Positive . P* . Lymphovascular invasion < 0·001  Present 236 (53·4) 206 (46·6)  Absent 1173 (88·1) 158 (11·9) Depth of invasion < 0·001  SM1 321 (91·5) 30 (8·5)  SM2 412 (85·8) 68 (14·2)  SM3 676 (71·8) 266 (28·2) Tumour size (cm) < 0·001  < 1 36 (88) 5 (12)  1–2 297 (89·7) 34 (10·3)  2–3 376 (83·9) 72 (16·1)  > 3 700 (73·5) 253 (26·5) Gross appearance < 0·001  Elevated 325 (70·9) 133 (29·1)  Flat 281 (84·1) 53 (15·9)  Depressed 803 (81·9) 178 (18·1) Differentiation 0·003  Well differentiated 153 (89·5) 18 (10·5)  Moderately differentiated 521 (80·2) 129 (19·8)  Poorly differentiated 723 (77·7) 208 (22·3) Perineural invasion < 0·001  Yes 113 (70·6) 47 (29·4)  No 1296 (80·3) 317 (19·7) . Lymph node metastasis . . Negative . Positive . P* . Lymphovascular invasion < 0·001  Present 236 (53·4) 206 (46·6)  Absent 1173 (88·1) 158 (11·9) Depth of invasion < 0·001  SM1 321 (91·5) 30 (8·5)  SM2 412 (85·8) 68 (14·2)  SM3 676 (71·8) 266 (28·2) Tumour size (cm) < 0·001  < 1 36 (88) 5 (12)  1–2 297 (89·7) 34 (10·3)  2–3 376 (83·9) 72 (16·1)  > 3 700 (73·5) 253 (26·5) Gross appearance < 0·001  Elevated 325 (70·9) 133 (29·1)  Flat 281 (84·1) 53 (15·9)  Depressed 803 (81·9) 178 (18·1) Differentiation 0·003  Well differentiated 153 (89·5) 18 (10·5)  Moderately differentiated 521 (80·2) 129 (19·8)  Poorly differentiated 723 (77·7) 208 (22·3) Perineural invasion < 0·001  Yes 113 (70·6) 47 (29·4)  No 1296 (80·3) 317 (19·7) Values in parentheses are percentages. SM1, infiltration into upper third of submucosa SM2, infiltration into middle third of submucosa SM3, infiltration into lower third of submucosa. * χ2 test. Open in new tab Table 3 Multivariable analysis of predictive factors for lymph node metastasis in early gastric cancer invading the submucosa . Hazard ratio . P . Lymphovascular invasion 4·76 (3·39, 6·70) < 0·001 Depth of invasion SM3 2·41 (1·46, 3·99) 0·001 Tumour size > 3 cm 2·29 (1·44, 3·64) < 0·001 Elevated gross appearance 2·24 (1·03, 3·30) < 0·001 Poorly differentiated 2·10 (1·13, 3·89) 0·005 Perineural invasion 1·71 (1·04, 2·81) < 0·001 . Hazard ratio . P . Lymphovascular invasion 4·76 (3·39, 6·70) < 0·001 Depth of invasion SM3 2·41 (1·46, 3·99) 0·001 Tumour size > 3 cm 2·29 (1·44, 3·64) < 0·001 Elevated gross appearance 2·24 (1·03, 3·30) < 0·001 Poorly differentiated 2·10 (1·13, 3·89) 0·005 Perineural invasion 1·71 (1·04, 2·81) < 0·001 Values in parentheses are 95 per cent confidence intervals. SM3, infiltration into lower third of submucosa. Open in new tab Table 3 Multivariable analysis of predictive factors for lymph node metastasis in early gastric cancer invading the submucosa . Hazard ratio . P . Lymphovascular invasion 4·76 (3·39, 6·70) < 0·001 Depth of invasion SM3 2·41 (1·46, 3·99) 0·001 Tumour size > 3 cm 2·29 (1·44, 3·64) < 0·001 Elevated gross appearance 2·24 (1·03, 3·30) < 0·001 Poorly differentiated 2·10 (1·13, 3·89) 0·005 Perineural invasion 1·71 (1·04, 2·81) < 0·001 . Hazard ratio . P . Lymphovascular invasion 4·76 (3·39, 6·70) < 0·001 Depth of invasion SM3 2·41 (1·46, 3·99) 0·001 Tumour size > 3 cm 2·29 (1·44, 3·64) < 0·001 Elevated gross appearance 2·24 (1·03, 3·30) < 0·001 Poorly differentiated 2·10 (1·13, 3·89) 0·005 Perineural invasion 1·71 (1·04, 2·81) < 0·001 Values in parentheses are 95 per cent confidence intervals. SM3, infiltration into lower third of submucosa. Open in new tab There was no relationship between lymph node metastasis and age (P = 0·528), sex (P = 0·435), tumour location (P = 0·205), p53 mutation (P = 0·604), or expression of HER1 (P = 0·615) or HER2 (P = 0·824). Algorithm for identifying submucosal gastric cancer with no lymph node metastasis The 1773 patients were categorized on the basis of predictive factors in order of statistical significance: lymphovascular invasion, depth of invasion and tumour size (2 cm). They were then subdivided into three subgroups according to well/moderately/poorly differentiated histological findings (Fig. 1). Metastatic lymph nodes were observed in four (3·8 per cent) of 105 patients who met the classical extended criteria of ESD; all of them had moderately differentiated histology. No metastatic lymph nodes were observed in either of the following groups: well differentiated SM1 cancer of any size without lymphovascular invasion, or well differentiated SM2 cancer of 2 cm or less without lymphovascular invasion. Fig. 1 Open in new tabDownload slide Categorization of 1773 patients with submucosal gastric cancer and 364 patients with nodal metastases according to predictive factors for lymph node metastasis. Values in parentheses indicate the percentage of lymph node metastases. LVI, lymphovascular invasion; SM1, infiltration into upper third of submucosa; SM2, infiltration into middle third of submucosa; SM3, infiltration into lower third of submucosa; WD, well differentiated; MD, moderately differentiated; PD, poorly differentiated Discussion Many patients with early gastric cancer have metastatic lymph nodes, and lymph node metastasis is the most important prognostic factor for survival in resectable gastric adenocarcinoma12,13. With advances in laparoscopic surgery and endoscopic treatment, the preoperative prediction of nodal metastasis in early gastric cancer has become very important to determine the appropriate treatment modality. This is particularly true for submucosal tumours because they have a higher rate of lymph node metastasis than mucosal cancers. When early gastric cancers are subdivided into mucosal and submucosal carcinomas, the risk factors for nodal metastasis are quite different between the two groups14. The present study assessed the relationship of predictive clinicopathological factors, including p53 mutation and HER1/HER2 expression, with lymph node metastasis in patients with submucosal cancer in order to identify a group with submucosal tumours at low risk of nodal involvement. In agreement with the results of two previous studies2,4, the present analysis demonstrated that the presence of lymphovascular invasion and larger tumour size significantly increased the risk of lymph node metastasis in submucosal gastric cancer. The depth of invasion was also an important predictive factor, in agreement with other studies15,16. It is generally accepted that early gastric cancer with a depressed morphology is associated with an increased risk of nodal metastasis2,16,17. In contrast to this, the present study showed that elevated tumours were more frequently associated with lymph node metastasis than the flat or depressed type. Most previous studies have classified macroscopic tumours into elevated (type I or IIa), flat (IIb), depressed (IIc or III) and mixed types (other). In the present series, tumours were classified into three types, depending on their dominant morphology. The mixed type is commonly encountered, and often subdivided. Consequently, the classification used in the present study might be more useful. In the present study, type IIa + IIc lesions were classified in the elevated group instead of the mixed type, and this difference may explain the discrepancy between the results. When the present tumours were reclassified according to the criteria of other studies, the depressed type had the highest rate of lymph node metastasis (22·2 per cent). The elevated type also had a high frequency of nodal metastasis (18·9 per cent). This may be because submucosal tumours with an elevated appearance have a larger tumour burden than the other types, resulting in an increased chance of lymph node metastases, contrary to findings in mucosal cancer. Most previous studies divided early cancers into differentiated/undifferentiated types or used the Laurén classifications. Although categorization into well/moderately/poorly differentiated histology was relatively subjective compared with the other two classifications, the categorization used in the present study provided the strongest predictive value. Metastatic lymph nodes were observed in fewer than 4 per cent of patients meeting the classical extended criteria of the ESD; they all had moderately differentiated histology. No patient with well differentiated SM1 cancer without lymphovascular invasion had nodal metastases, regardless of tumour size. In addition, patients with well differentiated SM2 cancers of 2 cm or less in size, and without lymphovascular involvement, had no metastatic lymph nodes. Therefore, endoscopic resection might be suitable for such patients. As a criterion for SM1, the present study adopted the upper third of the submucosa instead of 500 µm from the muscularis mucosa. Although the direct measurement of the submucosal infiltration depth is more objective than the traditional SM category, it can be altered during procedures such as endoscopic saline injection or specimen handling. In addition, two studies reported that there was limited correlation between the SM1/2/3 categories and the direct measurement6,15. At present, it is impossible to estimate the exact infiltrating depth in the submucosa before surgery, and direct depth measurements after endoscopic resection have limited accuracy. Therefore, criteria for ESD should be cautious and conservative. On the other hand, several Korean studies have reported postoperative complication rates of laparoscopy-assisted gastrectomy of 10–25 per cent and major complication rates of 2–5 per cent18–20. In this context, ESD could be considered for patients with a high operative risk. This study revealed that all moderately differentiated SM1 cancers without lymphovascular invasion, regardless of size, had a 5·0 per cent (6 of 120) rate of lymph node metastasis, and moderately differentiated SM2 cancer of 2 cm or less in size without lymphovascular invasion had a rate of 6 per cent (2 of 35). Therefore, ESD might be an alternative treatment for such tumours in elderly patients or those with severe cardiopulmonary compromise. Disclosure The authors declare no conflict of interest. References 1 Ono H , Kondo H, Gotoda T, Shirao K, Yamaguchi H, Saito D et al. Endoscopic mucosal resection for treatment of early gastric cancer . Gut 2001 ; 48 : 225 – 229 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Gotoda T , Yanagisawa A, Sasako M, Ono H, Nakanishi Y, Shimoda T 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 : 219 – 225 . 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Published by John Wiley & Sons Ltd This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) © 2013 British Journal of Surgery Society Ltd. Published by John Wiley & Sons Ltd
TI - Suitability of endoscopic submucosal dissection for treatment of submucosal gastric cancers
JO - British Journal of Surgery
DO - 10.1002/bjs.9051
DA - 2013-03-01
UR - https://www.deepdyve.com/lp/oxford-university-press/suitability-of-endoscopic-submucosal-dissection-for-treatment-of-QsqD0MO2cx
SP - 668
EP - 673
VL - 100
IS - 5
DP - DeepDyve
ER -