病理科 實 證 期 刊 閱 讀 報 告 EBM-style Journal Reading 報告人： 蘇子誠 指導臨床教師：朱斾億醫師 日期： 2009/4/20 地點：病理科會議室

2 Clinical Scenario （臨床情境） Lymphatic invasion is known as an independent predictor of lymph node metastasis in gastric cancer. However, the diagnosis of lymphatic invasion is sometimes difficult by hematoxylin-eosin (H&E) staining because complete obliteration of the lymphatic lumen by cancer cells is not diagnosed as lymphatic invasion. Furthermore, retraction artifacts due to tissue shrinkage during fixation are sometimes confused as the true tumor emboli in lymphatic vessels. More recently, a new monoclonal antibody, designated as D2-40, became available to identify the tumor emboli in the lymphatic vessels in paraffin sections and was proved to be a specific marker for the lymphatic vessels Whether increase identified rate of lymphatic permeation with IHC stain of D2-40 compared with H&E stain?

3 Clinical Uncertainty → PICO 問題 Does patient with gastric carcinoma increase sensitivity for identification of lymphatic permeation with immunohistochemical stain of D2-40 compared with conventional H&E stain?

4 臨床個案的 PICO Patient / Problem Patient with gastric carcinoma InterventionD2-40 IHC staining ComparisonH&E staining Outcome sensitivity for identification of lymphatic permeation Type of Question: Diagnosis

5 Search Terms & Strategy: （搜尋關鍵字與策略） 資料庫： PubMed 搜尋日期： 2009/4/10 搜尋關鍵字與隅策略： (("stomach"[MeSH Terms] OR "stomach"[All Fields] OR "gastric"[All Fields]) AND ("carcinoma"[MeSH Terms] OR "carcinoma"[All Fields])) AND #1 

6 Best available evidence: （挑選可獲得之最佳研究證據） Citation/s: Evaluation of lymphatic invasion in primary gastric cancer by a new monoclonal antibody, D2-40 Lead author's name : Yutaka Yonemura MD, PhDa,*, Yoshio Endou PhD

7 The Study: （研究效度） - 1 Seventy-eight patients with primary gastric cancer. All patients underwent gastrectomy with lymph node dissection. All surgical specimens of the primary tumors and regional lymph nodes were examined histologically by routine hematoxylin-eosin (H&E) staining. All statistical calculations were performed using the SPSS statistical software (SPSS, Inc, Chicago, Ill). The v2 test was used to determine the significance of intergroup differences. Level of Evidence: 3b

8 The Study: （研究效度） - 2 本篇文獻的 PICO (T) Patient / Problem Patient of gastric adenocarcinoma Intervention Lymphatic permeation identified by H&E staining Comparison Lymphatic permeation identified by IHC staining of D2-40 Outcome Sensitivity for lymph node metastasis by the lymphatic invasion Sensitivity for the prediction of lymph node metastasis from the lymphatic invasion status Time x

9 The Evidence: （研究重要結果） - 1 Specimens examined by H&E staining showed a false-negative rate of lymphatic invasion in 21.8% (17/78) and a false-positive rate in 5.1% (4/78). Positive rate of lymphatic invasion by H&E staining was 27% (21/78), and that by D2-40 was 44% (34/78) ( P<.001). Sensitivity for lymph node metastasis by the lymphatic invasion diagnosed by D2-40 was significantly higher (89%, 24/27) than by H&E staining (41%, 11/27).

10 The Evidence: （研究重要結果） - 2 D2-40 Lym(-)Lym(+)total H&ELym(-) H&ELym(+)41721 total443478

11 The Evidence: （研究重要結果） - 3 D2-40 Ly+Ly- LN metaN+24327Sensitivity, 89% (24/27) N Specificity, 78% (38/51) Accuracy, 79% (62/78) H&E Ly+Ly- LN metaN Sensitivity, 55% (15/27) N064551Specificity, 88% (45/51) Accuracy, 77% (60/78)

12 Comment & Discussion: -1 VEGFR-3 and LYVE-1 are also specific markers for lymphatic endothelial cells, but the available antibodies against VEGFR-3 or LYVE-1 do not react with the paraffinembedded tissues. As reported by Kahn et al, D2-40 is a new selective marker of lymphatic endothelial cells and does not react with endothelial cells of blood vessels. Furthermore, immunoreactivity by D2-40 antibody was clearly detected on all sections from formalin-fixed and paraffin-embedded blocks. By using D2-40 immunostaining, false-positive rate for lymphatic invasion by H&E staining was 5% (4/78), and the retraction artifact around the cancer nests may be initially spuriously diagnosed as lymphatic invasion.

13 Comment & Discussion: -2 In contrast, a tumor embolus that obliterated the lymphatic lumen could be clearly diagnosed by D2-40 immunoreactivity, and 17 tumors, which had been diagnosed as no lymphatic invasion by H&E staining, were correctly diagnosed as having lymphatic invasion after D2-40 staining. In contrast, only 17 (50%) of 34 lymphatic invasions, confirmed by D2-40 staining, were correctly diagnosed by H&E staining. Lymph node metastasis was significantly related with the tissue status of lymphatic invasion, which were diagnosed by D2-40 immunohistochemistry. Sensitivity of lymph node metastasis predicted by the lymphatic invasion status in D2- 40 staining was 89% and was higher (41%) than that in H&E staining. These results indicate that the findings of lymphatic invasion by D2-40 are more reliable to predict lymph node metastasis than by H&E staining.

14 回到臨床個案情境 Clinical bottom line 臨床決策底線 The diagnosis of lymphatic invasion by D2-40 is more sensitive than H&E staining. Sensitivity for the prediction of lymph node metastasis from the lymphatic invasion status in primary tumor by D2-40 was significantly higher than by H&E staining.  證據等級 3b, 建議等級 B

15 結 論 （標題 Title ） The use of D2-40 immunoreactions for the routine evaluation of lymphatic invasion in gastric cancer is recommended Update By: April. 20, 2009

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