title: Immunohistochemical and genetic features of gastric and metastatic liver gastrointestinal stromal tumors: sequential analyses.
abstract: Metastatic gastrointestinal stromal tumors (GIST) have an extremely poor prognosis; however, their immunohistochemical and genetic features have not been assessed satisfactorily and the mechanisms responsible for their high malignant potential remain unclear. We examined the immunohistochemical differences between gastric GIST and metastatic lesions in the liver of four patients who had undergone a postgastrectomy hepatectomy for metachronous liver metastases. We also carried out genetic analysis of the tumors in three of the four cases. In all cases, the immunoreactivity profiles, including KIT (CD117), CD34, smooth muscle actin (SMA), desmin, S-100 and vimentin, were similar between the gastric and metastatic tumors, but the Ki67 labeling index in the metastatic GIST was higher than that of the primary GIST. Interestingly, in the case who had received neoadjuvant imatinib therapy before gastrectomy, its therapeutic effect was observed in most of the primary lesion, with the exception of a specific small area with high cellularity. Genetic analysis revealed no acquired mutations in the c-kit or PDGFRA genes in the metastatic lesions in any of the patients, but loss of heterozygosity (LOH) of the c-kit gene was observed mainly in the metastatic tumors in two of the three cases. Furthermore, in the case of neoadjuvant imatinib therapy, LOH of the c-kit gene was shown in the high cellularity area in the primary lesion and metastatic liver GIST. It is suggested that LOH of the c-kit gene is an important event that leads to imatinib resistance and metastatic progression of GIST. In conclusion, both gastric and metastatic GIST had almost the same immunohistochemical features, except for their proliferative activity, and LOH of the c-kit gene played an important role in the process of liver metastasis.
authors.affiliation: Second Department of Surgery, Hamamatsu University School of Medicine, Handayama, Hamamatsu 431-3192, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Yamashita
authors.forename: Toshiki
authors.initials: T
authors.lastname: Kawabata
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hiramatsu
authors.forename: Kenji
authors.initials: K
authors.lastname: Kondo
authors.forename: Megumi
authors.initials: M
authors.lastname: Baba
authors.forename: Manabu
authors.initials: M
authors.lastname: Ohta
authors.forename: Kinji
authors.initials: K
authors.lastname: Kamiya
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Tanaka
authors.forename: Shohachi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kitagawa
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kitagawa
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Sugimura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Konno
mesh_terms: D000368:Aged; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D006801:Humans; D000068877:Imatinib Mesylate; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000378:metabolism*; D010879:Piperazines / Q000627:therapeutic use; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use; D017386:Sequence Homology, Amino Acid; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit