title: Pleomorphic phenotypes of gastrointestinal stromal tumors at metastatic sites with or without imatinib treatment.
abstract: Secondary resistance of gastrointestinal stromal tumors (GISTs) to tyrosine kinase inhibitors occurs after several years' administration. However, the mechanism of resistance has not been fully clarified. In this study, we analyzed the genotypes and the histologic and immunohistochemical phenotypes of metastatic GISTs with and without imatinib treatment, and clarified the pleomorphic nature of metastatic GISTs. We examined 31 autopsy cases in which the patients died of multiple metastases of GISTs, and two surgically resected specimens with and without imatinib treatment. A total of 152 primary and metastatic lesions in 33 cases of GISTs were examined for histologic and immunohistochemical expression of KIT and CD34. We analyzed the expression of other receptor tyrosine kinases (RTKs) in KIT-negative lesions, including human EGFR-related 2 (HER2), epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (MET), platelet-derived growth factor receptor-alpha (PDGFRA), and platelet-derived growth factor receptor-beta (PDGFRB). Fifteen lesions in seven cases (9.9%) lacked KIT expression, and 74 (49%) in 22 cases lacked CD34 expression. Eight KIT-negative lesions in five cases expressed PDGFRB, one of which also expressed EGFR, and three lesions in one case expressed MET. Results for the other RTKs were negative. Missense point mutations at PDGFRB gene exon 12 were detected in one PDGFRB-positive case. Our results indicate that histomorphology, immunohistochemical phenotypes, and genotypes of metastatic GISTs vary among lesions, even in cases without imatinib treatment. A KIT-independent mechanism, such as activation of other RTKs, might participate in the proliferation of late-stage GISTs and might be a cause of secondary imatinib resistance.
authors.affiliation: Department of Diagnostic Pathology, Graduate School of Medicine, Gunma University, Gunma, Japan.
authors.forename: Kazuha
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Sakurai
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kanda
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sakuma
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Hishima
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Hironaka
authors.forename: Takeo
authors.initials: T
authors.lastname: Bamba
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Keira
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Takano
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
authors.forename: Tadashi
authors.initials: T
authors.lastname: Hasegawa
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
mesh_terms: D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D066246:ErbB Receptors; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta