Detection of clonal histiocytes in langerhans cell histiocytosis: Biology and clinical significance

Although the first clinical description of Langerhans cell histiocytosis (LCH) was published over a century ago, the aetiology and pathogenesis of this enigmatic disorder are still remained unknown. Viral immunological, neoplastic and other pathogenetic mechanisms have been considered, but none has been proven. The prevailing opinion is that LCH is a reactive disorder rather than a neoplastic process, but this presumption has never been definitively tested. A key feature of a neoplasm is its clonal derivation from a single cell. To determine if LCH is a polyclonal reactive or a clonal disorder, we and others have recently used molecular biological techniques to assess clonality in LCH. Using X chromosome-linked DNA probes that can detect clonal or polyclonal X chromosome inactivation patterns in female tissues, clonal CD1a+ histiocytes have now been detected in the lesional tissues in each of 16 females affected with LCH. Most of these patients were studied prior to the initiation of therapy. Lymphoid clonality was excluded in all cases in which it was studied, confirming that the clonal cells in LCH are the CD1a+ dendritic cells presumed to be pivotal in this disorder. Two distinct lesions (a pre-treatment bone biopsy and a lymph node biopsied 3 years later) have been studied in only one case to date; the same clonal pattern of X chromosome inactivation was observed consistent with persistence of the same clone during this patient's disease course. Unexpectedly, clonal histiocytes were detected in all forms of LCH (in infants with 'disseminated disease' involving lymph nodes, liver, spleen, and bone marrow; in females with multisystem disease involving skin, bones, and other organs; and in females with unifocal bone disease). Although the biological significance of the detection of clonality in the histiocytic lineage is not yet fully understood. these data suggest that LCH may be a clonal neoplastic disorder with highly variable biological behaviour and clinical severity. As all forms of LCH appear to be clonal, assessment of clonality at diagnosis will not be useful in predicting outcome in individual patients. However, this discovery provides clear directions for studies that must now be undertaken to understand more fully the biological and clinical significance of clonality in LCH.