Background: The pathogenesis of Langerhans cell histiocytosis (LCH), a disease characterized by an abnormal accumulation of the dendritic Langerhans cells, is still unknown. Based on the monoclonality of the CD1a+ cell and reports of familial clustering, it is hypothesized that a genetic alteration at a cellular level may be causative. This genetic change may have an effect on the cellular mechanisms controlling proliferation and apoptosis. Materials and Methods: LCH-lesions were studied for the expression of Ki-67, present in the nucleus of proliferating cells. Furthermore, the expression of cell cycle-related gene products TGF-β receptor I and II, MDM2, p53, p21, p16, Rb, and Bcl2 were studied. The TGF-βR genes play a role in tumor suppression, whereas Bcl2 inhibits apoptosis. The remaining genes are part of either the p53-p21 and/or p16-Rb pathways, which induce cell cycle arrest or apoptosis in response to DNA damage. Results: In 30 biopsies the diagnosis of LCH could be confirmed on the basis of CD1a positivity (27 bone and 3 skin). All cases showed scattered nuclear-positive staining for the proliferation marker Ki-67. In more than 90% (n ≥ 27) of these cases, expression of TGFβ receptor I and II, MDM2, p53, p21, p16, Rb, and Bcl2 was detected in lesional LCH cells. The overexpression was in general heterogeneous, ranging from limited focal staining of scattered cells within the lesion to strong diffuse staining. Conclusions: These findings suggest that the cellular mechanisms that sense and respond to DNA-damage, namely the p53-p21 pathway and the p16-Rb pathway, are activated. The expression of Ki-67 indicates that the cells in LCH are proliferating. The observed overexpression of Bcl2 may play a role in the activation of p53 and p16 and/or the arrest of apoptosis.

, , , , , , , , , ,,
Journal of Pediatric Hematology / Oncology
Department of Immunology

Schouten, B., Egeler, M., Leenen, P., Taminiau, A., van den Broek, L., & Hogendoorn, P. (2002). Expression of cell cycle-related gene products in Langerhans cell histiocytosis. Journal of Pediatric Hematology / Oncology, 24(9), 727–732. doi:10.1097/00043426-200212000-00009