Rationale for the application of RANKL inhibition in the treatment of Langerhans cell histiocytosis.

Abstract

Langerhans Cell Histiocytosis (LCH) is a rare disease exhibiting both neoplastic and inflammatory features including abundant cytokine secretion both at the lesional and systemic level. Evaluation of RANKL expression within LCH lesions in various tissues. Cross-sectional study involving paraffin blocks from the diagnostic biopsies of adults with LCH. The study was conducted among patients followed in an adult outpatient clinic. Eleven patients with active LCH, who were 41.27 ± 3.44 years old, and five patients who were 46.8 ± 7.19 years old with non-LCH diagnosis serving as controls. RANKL, p65 and CD1a immunostaining of deparaffinized sections from LCH lesions and control tissues. Comparison of RANKL and p65 expression between LCH lesions, as indicated from concomitant CD1a immunostaining, and control tissue counterparts. A focal positive granular cytoplasmic RANKL staining was found at all lesional sites in a number of cells of the pathological infiltrate, mostly with morphologic features of pathological Langerhans cells (LCs). Compared to control tissues, RANKL positivity in LCH cases showed an excess of staining, both in intensity of staining and the number of stained cells, especially in areas of pathologic infiltration. RANKL staining also coincided with strong p65 NFκB nuclear positivity, especially in lesional infiltrates. RANKL is highly expressed in active LCH at the lesional level, concomitant to p65 NFκB activation. The use of RANKL inhibition as a rational therapeutic approach of the disease now needs further clinical evaluation.