Albert J. Kovatich

Gastrointestinal stromal tumors (GISTs) represent a distinct and the most important subset of mesenchymal tumors of the GI tract. These tumors are both phenotypically and genotypically different from true leiomyomas and usually express CD34, a hematopoietic progenitor cell antigen. CD34, however, is also present in a wide variety of fibroblastic and endothelial cell tumors. In this immunohistochemical study of CD117, we evaluated 85 cases of GIST and more than 150 other mesenchymal tumors, including leiomyomas and schwannomas. CD117, the c-kit proto-oncogene product, is expressed in subsets of hematopoietic stem cells, mast cells, melanocytes, and interstitial cells of Cajal of the GI tract. CD117 was almost always (85%) expressed in both benign and malignant GISTs. CD117 was observed both in the spindle cell and epithelioid subtypes of GISTs in all locations. In addition to reacting with the CD34-positive GISTs, CD117 was positive in some CD34-negative cases. Approximately one-third of GISTs coexpressed CD117 and smooth muscle actins. In contrast, true leiomyomas (desmin and actin-positive) and schwannomas in both GI and peripheral locations were consistently negative for CD117. Solitary fibrous tumors and Kaposi's sarcomas, which are typically CD34 positive, were consistently CD117 negative. Among the CD34-positive tumors that showed occasional CD117 reactivity were dermatofibrosarcoma protuberans (1 of 7) and hemangiopericytoma (2 of 10). Other mesenchymal tumors that were variably CD 117 positive included clear cell sarcoma (7 of 15), metastatic melanoma (9 of 25), and malignant fibrous histiocytoma (1 of 20). These results indicate that CD117 is a specific marker for GIST among tumors that occur in the GI tract and adjacent regions. CD117 expression also separates GISTs from true leiomyomas and gastric schwannomas.

Gastrointestinal stromal tumor or smooth muscle tumor (GIST) is the designation for a major subset of gastrointestinal mesenchymal tumors that histologically, immunohistochemically, and genetically differ from typical leiomyomas, leiomyosarcomas, and schwannomas. Because GISTs, like the interstitial cells of Cajal, the gastrointestinal pacemaker cells, express CD117 (c-kit protein), the origin of GISTs from the interstitial cells of Cajal has been recently proposed. Comparison of GISTs primary in the omentum and mesentery to GISTs primary in the tubular gastrointestinal tract is of particular diagnostic and histogenetic interest in view of the possible similarity of these tumors with the GIST group. In this study, we analyzed 14 omental and 12 mesenteric primary mesenchymal tumors representing smooth muscle tumors or GISTs. These tumors were phenotypically compared with gastric and small intestinal GISTs, leiomyomas of the esophagus, and leiomyosarcomas of the retroperitoneum. Most (13 of 14) omental and mesenteric (10 of 12) tumors showed histologic features similar to GISTs with elongated spindle cells or epithelioid cells with high cellularity; most of these tumors showed low mitotic activity. Omental and mesenteric GISTs were typically positive for CD117 and less consistently for CD34. They often showed alpha-smooth muscle actin reactivity but were virtually negative for desmin and S-100 protein. One omental and two mesenteric tumors showed features of leiomyosarcoma with ovoid, less elongated nuclei, cytoplasmic eosinophilia; all these tumors had significant mitotic activity. These tumors were positive for alpha-smooth muscle actin and two of them for desmin, but all were negative for CD34 and CD117, similar to retroperitoneal leiomyosarcomas. Tumor-related mortality occurred in the group of mesenteric GISTs, but not in the group of omental GISTs. In contrast, all three patients with a true leiomyosarcoma of the omentum or mesentery had documented liver metastases or died of tumor. In summary, we show that tumors phenotypically identical with GISTs occur as primary tumors in the omentum and mesentery. The occurrence of CD117-positive tumors outside the gastrointestinal tract militates against an origin of these tumors exclusively from the interstitial cells of Cajal.

Defective DNA mismatch repair in human tumors leads to genome-wide instability of microsatellite repeats and a molecular phenotype referred to as microsatellite instability (MSI). MSI has been reported in a variety of cancers and is a consistent feature of tumors from patients with hereditary non-polyposis colorectal cancer. Approximately 20% of cancers of the uterine endometrium, the fifth most common cancer of women world-wide, exhibit MSI. Although the frequency of MSI is higher in endometrial cancers than in any other common malignancy, the genetic basis of MSI in these tumors has remained elusive. We investigated the role that methylation of the MLH1 DNA mismatch repair gene plays in the genesis of MSI in a large series of sporadic endometrial cancers. The MLH1 promoter was methylated in 41 of 53 (77%) MSI-positive cancers investigated. In MSI-negative tumors on the other hand, there was evidence for limited methylation in only one of 11 tumors studied. Immunohistochemical investigation of a subset of the tumors revealed that methylation of the MLH1 promoter in MSI-positive tumors was associated with loss of MLH1 expression. Immunohistochemistry proved that two MSI-positive tumors lacking MLH1 methylation failed to express the MSH2 mismatch repair gene. Both of these cancers came from women who had family and medical histories suggestive of inherited cancer susceptibility. These observations suggest that epigenetic changes in the MLH1 locus account for MSI in most cases of sporadic endometrial cancers and provide additional evidence that the MSH2 gene may contribute substantially to inherited forms of endometrial cancer.