LANGERHANS-CELL HISTIOCYTOSIS (HISTIOCYTOSIS-X) - A CLONAL PROLIFERATIVE DISEASE

Background. The lesions of Langerhans'-cell histiocytosis (histiocytos is X), a proliferative histiocytic disorder of unknown cause, contain histiocytes similar in phenotype to dendritic Langerhans' cells. The d isease ranges in severity from a fatal leukemia-like disorder to an is olated lytic lesion of bone. Intermediate forms of the disease are usu ally characterized by multiorgan involvement, diabetes insipidus, and a chronic course. Methods. To determine whether Langerhans' histiocyto sis is a polyclonal reactive disease or a clonal disorder, we used X-l inked polymorphic DNA probes (HUMARA, PGK, M27 beta[DXS255], and HPRT) to assess clonality in lesional tissues and control leukocytes from 1 0 female patients with various forms of the disease. Lymphoid clonalit y was also assessed by analysis of rearrangements at immunoglobulin an d T-cell-receptor gene loci. Results. The HUMARA assay detected clonal cells in the lesions of 9 of the 10 patients: 3 patients had acute di sseminated disease, 3 had unifocal disease, and 3 had intermediate for ms. The percentage of clonal cells closely approximated the percentage of CD1a-positive histiocytes in each lesion. Clonality was also confi rmed in two of nine cases with the PGK or M27 beta probe. Extreme cons titutional lyonization precluded assessment of clonality in the 10th c ase. Lymphoid clonality was ruled out in all cases. Conclusions. The d etection of clonal histiocytes in all forms of Langerhans'-cell histio cytosis indicates that this disease is probably a clonal neoplastic di sorder with highly variable biologic behavior. Thus, genetic mutations that promote clonal expansion of Langerhans' cells or their precursor s may now be identified.