Oncogene-induced senescence distinguishes indolent from aggressive forms of pulmonary and non-pulmonary Langerhans cell histiocytosis

The clonal/neoplastic nature of Langerhans cell histiocytosis (LCH) has recently been demonstrated by a high prevalence of BRAF mutations, including pulmonary LCH (PLCH). We hypothesized that BRAF-induced senescence, as demonstrated in nevi and melanoma, is involved in the pathogenesis of LCH and PLCH. In a series of pulmonary (19 cases) and non-pulmonary LCH (19 cases), including five aggressive cases, we investigated occurrence of the BRAF V600E mutation by molecular analysis and/or immunohistochemistry using a validated antibody (VE1). The expression of cell-senescence markers p16^INK4a and p21^CIP1/WAF1 was also immunohistochemically investigated. We demonstrated that 6/19 cases of LCH and 12/19 cases of PLCH were VE1 positive, matching with molecular analysis, and in all cases both p16^INK4a and p21^CIP1/WAF1 were expressed, irrespective of BRAF mutation status. Interestingly, all the aggressive cases did not express p16^INK4a, thus suggesting that loss of senescence control could be related to clinical aggressiveness of LCH, as in melanoma.