The clinicopathologic and immunohistochemical features in 120 cases of gastrointestinal stromal tumor (GIST) were reviewed. Excluding 24 cases of gastric schwannoma, 96 cases of GIST consisting of 62 benign tumors and 34 sarcomas (low grade, 17; high grade, 17), with 9 cases arising in the esophagus, 57 in the stomach, 28 in the small intestine, and 2 in the colon, were studied. All esophagus and colon tumors were benign and resembled a conventional leiomyoma histologically. However, the gastric and small intestine benign tumors mostly showed histologic features of cellular or epithelioid leio-myoma. Immunohistochemically, desmin caused a positive reaction in all esophagus and colon tumors, but only 26% of gastric and small intestine tumors. However, muscle-specific actin (HHF35) caused a positive reaction in most GIST (92%). The 10-year survival rates of the patients with gastric sarcoma and those with intestinal sarcoma were 74% and 17%, respectively. These results showed that histologic and immunohistochemical features were distinctly different, depending on the location in the gastrointestinal tract; that most GIST, excluding schwannoma, had smooth muscle differentiation; and that sarcomas had a more favorable prognosis when they occurred in the stomach rather than the intestine. Cancer 1992; 69947-955. The origin and differentiation of gastrointestinal stro-ma1 tumors (GIST) has been a source of recent speculation and controversy. Most GIST traditionally have been classified as smooth muscle tumors. Mazur and Clark' studied the histogenesis of such tumors with an emphasis on the presence of occasional tumors with schwannian differentiation based on features found during electron microscopic and immunohistochemical examination. Daimaru et a1.' also have clarified the actual existence of a distinctive entity termed "benign schwannoma" among GIST, and described its unique histologic features that included a strong positive reaction for S-100 protein, benign nuclear atypia of tumor cells, and a peripheral lymphoid cuffing of the tumor. However, most GIST still appear to lack unanimity in immunohistochemical finding^.^-^ The rate of positive reactions for smooth muscle markers such as des-min ranges from 0% to 53% in gastric tumors and from 0% to 44% in intestinal tumors. However, HHF35, a muscle-specific actin, has been recently introduced7 as a marker for virtually all muscle and muscle-derived cells; a few reports'~~ have shown that more than 60% of GIST had a positive reaction to this particular actin. GIST also are known for their wide variability in clinical behavior and for the difficulty in determining their malignant A large number of cases with complete follow-up are needed to establish reliable criteria of malignancy in these tumors. The current study was designed to elucidate the histogenesis of these tumors, by using various immuno-histochemical markers, and to identify parameters that will help in establishing the criteria of malignancy in the GIST. Materials and Methods One hundred twenty specimen...