Gastrointestinal stromal tumors: a spectrum of disease

Abstract

The majority of gastrointestinal stromal tumors (GIST) express c-kit, a growth factor receptor with tyrosine kinase activity. Mutations in the c-kit proto-oncogene may lead to constitutive ligand-independent activation of c-kit and subsequent neoplastic transformation. Selective tyrosine kinase inhibitors target this property of GIST and have become the standard chemotherapy for metastatic or unresectable tumors. The mainstay of treatment, however, continues to be complete surgical resection. Tyrosine kinase inhibitors may prove expedient for adjuvant therapy, and are currently the focus of clinical trials conducted by the ACOSOG, RTOG, and ACRIN. It is important to distinguish GISTs from other mesenchymal tumors of the GI tract because of differences in natural history, as well as the efficacy of treatments targeting the GIST tyrosine kinase.

Introduction

Gastrointestinal stromal tumors (GIST) are mesenchymal tumors of the gastrointestinal (GI) tract that are believed to originate from neoplastic transformation of the intestinal pacemaker cells (interstitial cells of Cajal; ICC) normally found in the bowel wall, or their precursors [1], [2]. Histologically, they appear to arise within the muscularis propria and consist predominantly of spindle and/or epithelioid cell types. These tumors may occur anywhere in the GI tract but are most commonly found in the stomach (39–70%) and small intestine (20–32%) [3], [4], [5]. They usually occur after the 4th decade, with most studies finding a mean age at diagnosis of about 60 years. The most common symptoms are vague upper abdominal pain (50–70%), gastrointestinal hemorrhage (20–50%), and abdominal mass [3], [6], [7], [8], [9].

GIST cells almost always (85–100%) express the c-kit protein (CD117 or c-kit) and frequently (70–80%) express the myeloid stem cell antigen CD34 [10], [11], [12], [13]. The c-kit gene product is a transmembrane receptor protein with an internal tyrosine kinase domain. C-kit is the receptor for the growth factor, stem cell factor (SCF; also known as steel factor or c-kit ligand). The receptor–ligand interaction between c-kit and SCF activates the internal tyrosine kinase which then phosphorylates intracellular proteins, leading to the activation of cellular signaling pathways. This cascade is believed to be important in the regulation of proliferation, apoptosis, adhesion and differentiation in several cell types including the ICC [14], [15].

The pathogenesis of GIST may involve a mutation in the c-kit proto-oncogene leading to ligand-independent constitutive activation of the c-kit receptor [12] and autophosphorylation of the c-kit protein. This constitutive signaling through the c-kit pathway is believed to result in the promotion of cell growth and/or inhibition of apoptosis. Mutations in exon 11 of the c-kit gene (long arm of chromosome 4), between the transmembrane and tyrosine kinase domains, have been identified in several series of malignant GISTs, however it is not a ubiquitous finding and cannot alone account for the pathogenesis [12], [13], [16]. Several studies have shown a correlation between exon 11 c-kit mutations and poor prognosis [13], [17], [18], and suggest that exon 11 mutations may be one of the strongest prognostic markers. Taniguchi et al. demonstrated in their series of 124 GISTs that patients with exon 11 mutation-positive GISTs had larger, more aggressive tumors with more necrosis and hemorrhage. Those patients with mutation-positive GISTs also were found to have more frequent recurrences and higher mortality than did those with mutation-negative GISTs [18].

There is no consensus within the surgical or pathology communities regarding the grading or classification of GIST. Malignant potential is not always predicted by conventional histologic factors. Because of this, some investigators have suggested that the terms benign and malignant GIST be replaced by low, intermediate, or high risk for malignant behavior [19], [20]. The most consistent variables historically used to predict aggressiveness have been tumor size and the mitotic index [4], [5], [19], [20]. Franquemont et al. [20] have proposed that the following features may portend a poor prognosis: size greater than or equal to $\text{5}\text{cm}$, mitoses greater than or equal to 2 per 10 high power fields (HPF), and proliferation index greater than 10% [21] (Table 1). Many others factors have also been investigated. Karyotypic or genetic markers such as deletions in chromosome 9p [22] or gain of function mutations in exon 11 of the c-kit gene have been correlated with malignant behavior in some studies [13], [17], [18] but require further validation. Tumor location has been identified as an important variable, as gastric GISTs appear to be less aggressive than esophageal GISTs or those located more distally in the gastrointestinal tract [4], [5]. Aneuploidy [5], the presence of metastases at presentation, tumors that are unresectable, male sex and older age have also been correlated with poor prognosis.

There is clearly a spectrum of biologic behavior within the disease with some tumors behaving more aggressively than others. Herein, two illustrative examples of GIST on either side of this disease spectrum are described along with management strategies including diagnostic modalities, histological findings, and adjuvant therapy.