title: Epstein-Barr virus positivity, not mismatch repair-deficiency, is a favorable risk factor for lymph node metastasis in submucosa-invasive early gastric cancer.
abstract: BACKGROUND
  Epstein-Barr virus (EBV)-associated gastric cancer (GC) and microsatellite-instability-high GC are associated with a low prevalence of regional lymph node metastasis (LNM). To evaluate the feasibility of endoscopic treatment of EBV-associated and/or microsatellite-instability-high early GC (EGC), we analyzed the risk factors for LNM using a large series (n = 756) of submucosa-invasive (SM) EGC.
  
  
  METHODS
  EBV-encoded RNA in situ hybridization (EBER ISH) and immunohistochemistry for four mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6) were performed. The clinicopathologic features and results of EBER ISH and immunohistochemistry were compared according to the LNM status.
  
  
  RESULTS
  Among the cases, 146 EGCs (19.3 %) showed LNM. EBV negativity, larger tumor size (greater than 2 cm), deeper level of submucosal invasion, submucosal invasion depth greater than 500 µm, presence of ulceration, and presence of lymphovascular invasion (LVI) were associated with LNM. However, the MMR deficiency was not correlated with LNM. On multivariate regression analysis, larger tumor size (greater than 2 cm; odds ratio 1.6, p = 0.030), deeper level of submucosal invasion (odds ratio 2.9, p = 0.001), LVI (odds ratio 7.4, p < 0.001), and EBV negativity (p = 0.020) were independent risk factors for LNM in SM EGCs.
  
  
  CONCLUSIONS
  EBV positivity was a favorable risk factor for LNM in SM EGC. However, MMR deficiency was not associated with the status of LNM. Thus, we suggest that examination with EBER ISH could be considered for endoscopic resected specimens, especially in cases of SM EGC showing no LVI and clear resection margins.
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
authors.forename: Eun Kyung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
authors.forename: Yon Hee
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
authors.forename: Jie-Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
authors.forename: Yoon Sung
authors.initials: YS
authors.lastname: Bae
authors.affiliation: Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
authors.forename: Yong Chan
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Cheong
authors.affiliation: Department of Surgery, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Noh
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea. kimhyunki@yuhs.ac.
authors.forename: Hyunki
authors.initials: H
authors.lastname: Kim
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000556:secondary* / Q000601:surgery / Q000821:virology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D053843:DNA Mismatch Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D055088:Early Detection of Cancer; D020031:Epstein-Barr Virus Infections / Q000175:diagnosis / Q000821:virology*; D005260:Female; D005500:Follow-Up Studies; D005743:Gastrectomy; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2 / Q000378:metabolism; D000070957:MutL Protein Homolog 1 / Q000378:metabolism; D051718:MutS Homolog 2 Protein / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery / Q000821:virology; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein
keywords: Early gastric carcinoma; Epstein–Barr virus; Lymph node metastasis; Microsatellite instability