Gastrointestinal Stromal Tumours: A Contemporary Review on Pathogenesis, Morphology and Prognosis

Abstract

Gastrointestinal stromal tumours (GISTs) comprise the largest subset of mesenchymal tumours of the digestive tract. Over the past 10 years, this group of tumours has emerged from a poorly understood neoplasm to a well defined tumour entity. The first accurate description of mesenchymal neoplasms of the gastrointestinal tract was in 1941 (Golden T & Stout AP, 1941). Traditionally, these tumours were thought to be derived from smooth muscle cells, based on their resemblance to smooth muscle tumours. They were referred to as leiomyomas, bizarre leiomyomas (Stout AP, 1976), cellular leiomyomas (Appelman, 1977) and leiomyosarcomas. However, the advent of electron microscopy revealed that only a few of them have convincing ultrastructural evidence of smooth muscle differentiation. In addition, the application of immunohistochemistry clearly demonstrated that many of these tumours lack the features of smooth muscle differentiation. This led Mazur and Clark in 1983 to introduce the generic designation “stromal tumour” (Mazur & Clark, 1983). A little later, in 1984, Herrera et al (Herrera et al., 1984) introduced the concept of “plexosarcoma” to acknowledge the existence of a small subset of stromal tumours with autonomic neuronal differentiation which became better known as gastrointestinal autonomic nerve tumours (GANTs) (Lauwers et al., 1993). A considerable controversy arose as to the line of differentiation these tumours take. Some tumours exhibit a myogenic phenotype, while others may show a neural differentiation, mixed or no differentiation at all, the so called “null phenotype”. Some enthusiasm was generated by the recognition that a significant proportion of stromal tumours express CD34 (Miettinen et al., 1995). However the diagnostic utility of this marker was hampered by its poor specificity. As a consequence of the lack of reproducible diagnostic criteria, GIST represented a generic term that indicates any mesenchymal tumour arising in the gastrointestinal tract. The recognition of the central role of c-kit mutations in the pathogenesis of GISTs (Hirota et al., 1998; Rubin et al., 2000) and in most cases the associated expression of KIT protein in these tumours has provided a reproducible genotypic and phenotypic marker (Kindblom et al., 1998). Therefore KIT (CD117 in the standardised terminology of leucocyte antigens) expression has emerged as a marker for discriminating GISTs from other mesenchymal