Characteristics of KIT-negative gastrointestinal stromal tumours and diagnostic utility of protein kinase C theta immunostaining

Abstract

Aims: To characterise KIT-negative gastrointestinal stromal tumours (GISTs) clinically, pathologically, immunohistochemically and genetically, and to establish the usefulness of protein kinase C theta (PKCθ) 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 α (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 PKCθ than KIT-positive GISTs; mutational analysis revealed that 30% of KIT-negative GISTs harboured a PDGFRA exon 18 mutation. Immunostaining on PKCθ showed that 93.9% of all GISTs expressed PKCθ protein. However, 21.9% of 64 mesenchymal tumours other than GIST also showed positivity on PKCθ.

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 PKCθ is a sensitive diagnostic marker for GIST, its usefulness is limited because of low sensitivity and low specificity in KIT-negative GISTs.