title: Low density of CD204-positive M2-type tumor-associated macrophages in Epstein-Barr virus-associated gastric cancer: a clinicopathologic study with digital image analysis.
abstract: Recent studies suggest that CD204-positive (CD204(+)) M2-type tumor-associated macrophages (TAMs) are associated with the aggressive behavior of various cancers. However, the clinicopathologic significance of tumor-infiltrating CD204(+) macrophages and their correlation with Epstein-Barr virus (EBV) in gastric cancer is unclear. Tissue microarrays were constructed from 119 surgically resected gastric cancer specimens (86 EBV-negative and 28 EBV-positive cases). After immunohistochemistry of CD204, the density of CD204(+) cells was calculated using image analysis software, and associations between CD204 and clinicopathologic factors including patient survival were examined. High CD204(+) cell density was significantly associated with several adverse prognostic factors, including older age (P = .008), advanced tumor depth (P < .001), lymph node metastasis (P < .001), presence of venous invasion (P < .001), and lymphatic invasion (P = .03). Low CD204(+) cell density was significantly associated with EBV infection. Advanced tumor depth and presence of lymph node metastasis were significantly associated with high CD204(+) cell density in both EBV-positive and EBV-negative subgroups. High CD204(+) cell density was significantly associated with shorter cancer-specific survival (P = .0015). In conclusion, a high density of CD204(+) TAMs was associated with the aggressive behavior and worse survival of gastric cancer. Low density of CD204(+) TAMs was associated with infection of EBV, which may explain the favorable outcome of EBV-associated gastric carcinoma. Our results suggest that a specific immune microenvironment may be associated with the biological behavior of gastric cancer and that EBV-associated gastric carcinoma is distinctive from other gastric carcinomas in tumor immunity.
authors.affiliation: Department of Chemotherapy, Gastroenterology Center, Gastroenterological Internal Medicine, the Cancer Institute Hospital of JFCR (Japanese Foundation for Cancer Research), Tokyo 135-8550, Japan; Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ichimura
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Abe
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan.
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Yamashita
authors.affiliation: Department of Genomic Pathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-0034, Japan.
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ishikawa
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Ushiku
authors.affiliation: Department of Gastroenterological Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Seto
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: mfukayama-tky@umin.ac.jp.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D005260:Female; D004854:Herpesvirus 4, Human / Q000302:isolation & purification*; D006801:Humans; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008264:Macrophages / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010641:Phenotype; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D051117:Scavenger Receptors, Class A / Q000032:analysis*; D012984:Software; D013274:Stomach Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000821:virology; D013997:Time Factors; D046888:Tissue Array Analysis; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; C495139:MSR1 protein, human; D051117:Scavenger Receptors, Class A
keywords: CD204; EBV-associated gastric cancer; Gastric carcinoma; Prognostic biomarker; Tumor-associated macrophage