title: Characteristics of KIT-negative gastrointestinal stromal tumours and diagnostic utility of protein kinase C theta immunostaining.
abstract: OBJECTIVE
  To characterise KIT-negative gastrointestinal stromal tumours (GISTs) clinically, pathologically, immunohistochemically and genetically, and to establish the usefulness of protein kinase C theta (PKC) as a diagnostic marker in KIT-negative GIST.
  
  
  METHODS
  252 consecutive cases of GIST were evaluated for clinicopathological characteristics and immunostained for various antibodies. Mutational analyses of KIT and platelet-derived growth factor receptor alpha (PDGFRA) were also performed in 62 cases.
  
  
  RESULTS
  20 (7.9%) GISTs showed negative immunostaining for KIT. KIT-negative GISTs were more likely to originate from omentum or peritoneum, have an epithelioid histology, and be classified as high risk. The overall survival rate of patients with KIT-negative GISTs (5-year survival rate 68.7% (SD 10.7%)) was lower than that of patients with KIT-positive GISTs (5-year survival rate, 79.9% (3.0%)) (p = 0.042, log-rank test). Negative KIT expression was an independent prognostic factor in multivariate Cox regression analysis when the risk of aggressive behaviour and the status of imatinib treatment were adopted as covariates. KIT-negative GISTs also showed lower expression rates of CD34, Bcl-2, and PKC than KIT-positive GISTs; mutational analysis revealed that 30% of KIT-negative GISTs harboured a PDGFRA exon 18 mutation. Immunostaining on PKC showed that 93.9% of all GISTs expressed PKC protein. However, 21.9% of 64 mesenchymal tumours other than GIST also showed positivity on PKC.
  
  
  CONCLUSIONS
  KIT-negative GISTs had characteristics that differ from those of KIT-positive GISTs, and negative KIT expression was an independent prognostic indicator for overall survival of patients. Although PKC is a sensitive diagnostic marker for GIST, its usefulness is limited because of low sensitivity and low specificity in KIT-negative GISTs.
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: H E
authors.initials: HE
authors.lastname: Lee
authors.forename: M A
authors.initials: MA
authors.lastname: Kim
authors.forename: H S
authors.initials: HS
authors.lastname: Lee
authors.forename: B L
authors.initials: BL
authors.lastname: Lee
authors.forename: W H
authors.initials: WH
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D014408:Biomarkers, Tumor / Q000032:analysis*; D001707:Biopsy, Needle; D016009:Chi-Square Distribution; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000032:analysis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008940:Mitotic Index; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000627:therapeutic use; D016016:Proportional Hazards Models; D011493:Protein Kinase C / Q000032:analysis* / Q000235:genetics; D000074121:Protein Kinase C-theta; D019009:Proto-Oncogene Proteins c-kit / Q000032:analysis* / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000032:analysis / Q000235:genetics; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D007527:Isoenzymes; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta