Detection of Clonal Lymphoid Receptor Gene Rearrangements in Langerhans Cell Histiocytosis

Langerhans cell histiocytosis (LCH), also known as histiocytosis X, is a rare human disorder characterized by an abnormal accumulation and/or clonal proliferation of Langerhans cells (LCs) in various body organs. The cellular origin of LCs has been a subject of considerable debate since their discovery. As specialized dendritic cells strategically located in epithelia, LCs are generally considered to be of myeloid origin from the bone marrow, however, recent studies in mice have shown that LCs can be derived from lymphoid-committed CD4(low) precursors, suggesting a lymphoid origin. In human LCH, concomitant or sequential occurrence of a lymphoid or myeloid malignancy has been occasionally reported, suggesting the presence of lineage plasticity and/or the possibility of transdifferentiation of 2 otherwise morphologically and immunophenotypically different neoplasms. To gain a better understanding of the pathogenesis and cellular origin of human LCH, we retrospectively investigated 46 well-characterized LCH cases to detect clonal rearrangements of T-cell receptor g gene (TRG@) and immunoglobulin heavy chain and kappa light chain genes (IGH@/IGK@). The study included 25 males and 21 females, with ages ranging from < 1 to 59 years. None (0/46) of the cases had a known history or concurrent B or T-cell lymphoma. Of 46 cases, 30% (14/46) cases had clonal IGH@ (4 cases), IGK@ (5 cases) or TRG@ (9 cases) gene rearrangements, respectively. Interestingly, of the 14 cases with at least one clonal rearrangement of lymphoid receptor genes, 3 LCH cases were shown to have both TRG@ and IGH@/IGK@ gene rearrangements, but failed to express T-cell or B-cell lineage specific or associated markers, suggesting lineage plasticity or infidelity of the neoplasm. Furthermore, all of the 14 cases were negative for t(14;18) by quantitative PCR analysis. In conclusion, our study shows that lymphoid receptor gene rearrangements can be detected in a subset of sporadic LCH cases, suggesting a possible lineage relationship between LCs and lymphoid cells or alternatively, derivation of LCs from lymphoid/myeloid precursors. The results provide genotypic evidence supporting the current notion of lineage plasticity of hematopoietic cells and their associated neoplasms.