When sarcomas break the rules: Evaluation of the CD117-negative gastrointestinal stromal tumor

We discuss the clinicopathologic features, pathogenesis, differential diagnosis, and diagnostic pitfalls of gastrointestinal stromal tumors (GISTs) of the upper gastrointestinal tract as illustrated by the case of a 55-year-old man with a jejunal mass. The most common mesenchymal neoplasm arising in the gastrointestinal tract, GIST has been defined broadly as a spindle cell lesion possessing either a KIT (CD117, a receptor tyrosine kinase) or platelet-derived growth factor receptor alpha mutation. Some GISTs, however, lack these specific mutations, instead harboring different changes (perhaps mutations affecting downstream signaling). GISTs are most common in the stomach (60%), followed by the jejunum and ileum (30%), duodenum (4%-5%), rectum (4%), colon and appendix (1%-2%), and esophagus (<1%). Rarely, apparent primary extragastrointestinal GISTs (in the abdominal or pelvic cavities) are seen. In the last few decades, elucidation of GIST pathogenesis has led to the development of effective directed treatment modalities. With this knowledge, clinicians frequently charge pathologists with the task of predicting a particular GIST's biologic potential, a notoriously difficult undertaking that varies by site. Although the CD117-negative GIST can cause considerable distress for the pathologist, attention to morphologic detail combined with a carefully considered ancillary test panel helps exclude mimics. In most cases, molecular techniques are not required for diagnosis, but in a subset of cases they are a useful prognostic tool. Current developments in the pharmacologic treatment of these tumors allow the pathologist, through accurate diagnosis and prognostic classification, to help direct the patient toward a potential cure.