Cellular origin of gastrointestinal stromal tumors: a study of 27 cases.
BACKGROUND
Interstitial cells of Cajal (ICCs), also known as pacemaker cells, are cells in the gastrointestinal tract that play a role in the control of gut motility. The ICCs express the c-kit proto-oncogene encoding a type III tyrosine kinase (KIT) receptor, a ligand that is known as stem cell factor (SCF). The maturation of ICCs is dependent on SCF-KIT interaction. The cellular origin, differentiation, nomenclature, and prognosis of gastrointestinal stromal tumors (GISTs) are controversial.


OBJECTIVE
To test the hypothesis that GISTs originate from CD34-positive stem cells and differentiate toward an ICC phenotype.


METHODS
We studied 27 cases of smooth muscle differentiated GISTs collected for 14 years (1985-1999), including 8 benign (leiomyoma), 15 malignant primary (leiomyosarcoma), and 4 metastatic to the liver. Immunohistochemical studies of selected lineage-directed monoclonal antibodies of c-kit (CD117), CD34, vimentin, desmin, alpha-actin, S100, and MIB-1 were performed on both normal and tumor tissues.


RESULTS
Immunoperoxidase stains of normal gastrointestinal tract showed both c-kit and CD34-positive cells surrounding the Auerbach ganglia plexus in the gastrointestinal tract. Twenty-seven of 27 tumors strongly expressed c-kit. Fourteen of 27 tumors were positive for CD34. Of the malignant GISTs, 14 of 19 were positive for CD34; of the benign tumors, 0 of 8 were positive for CD34. Thus, CD34 was the best indicator of malignant phenotype.


CONCLUSIONS
This is the first description of benign smooth muscle GISTs negative for CD34. The results of this study suggest that GISTs originate from CD34-positive stem cells and differentiate toward pacemaker cell phenotype. The lack of expression of CD34 in the benign GIST may indicate that benign GISTs are composed of more mature ICCs, whereas malignant GISTs are composed of dedifferentiated ICCs that express CD34-positive stem cells.
Wang
L
L
Departments of Pathology, University of California at Los Angeles, Harbor Medical Center, Torrance, CA, USA.
Vargas
H
H
French
S W
SW
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000737:chemistry / Q000209:etiology* / Q000473:pathology*; D006801:Humans; D007124:Immunoenzyme Techniques; D007889:Leiomyoma / Q000737:chemistry / Q000473:pathology*; D007890:Leiomyosarcoma / Q000737:chemistry / Q000556:secondary*; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D008875:Middle Aged; D000090063:Proto-Oncogene Mas; D017154:Stromal Cells / Q000737:chemistry / Q000473:pathology*
D018952:Antigens, CD34; D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas