Enhanced expression of c-myc and H-ras oncogenes in Letterer-Siwe disease. A sequential study using colorimetric in situ hybridization. Tissues from two patients with disseminated histiocytosis X (Letterer-Siwe disease) in which histiocytosis X cells exhibited histologic and cytologic features of malignancy were evaluated by in situ hybridization with the use of biotinylated nucleic acid probes to c-myc and H-ras oncogenes. Enhanced expression of these oncogenes was observed in mononucleated and multinucleated cells of histiocytosis X in the terminal proliferative phase but not in the early quiescent phase of Letterer-Siwe disease in both patients. Our findings indicate that deregulation of c-myc and H-ras in histiocytosis X are late events that likely confer a selective growth advantage to histiocytosis X cells. 