Histiocytosis class I and II Also in 1987, as a result of the collaborative efforts, a simple stratification system for practical use was introduced for LCH. The Writing Group of the Histiocyte Society recommended a division of the histiocytic disorders into three classes: Langerhans cell histiocytosis (LCH) (class I); non-Langerhans cell histiocytosis (class II); and malignant histiocytic disorders (class III). A minor revision of this classification has more recently been proposed, and the three major groups are now termed (1) dendritic cell-related disorders (of which LCH is by far the most common), (2) macrophage-related disorders, and (3) malignant disorders. ----------------------------------------------- three classes based on the pathologic cells present within the lesions. •Class I: Langerhans cell histiocytoses and other dendritic cell disorders. •Class II: non-Langerhans cell histiocytoses primarily con-sisting of hemophagocytic lymphohistiocytosis. •Class III: malignant histiocytosis. This system was revised in 1997 by the World Health Organization’s Committee on Histiocytic/Reticulum Cell Proliferations and the Reclassification Working Group of the Histiocyte Society. The central theme of this reclassification schema consisted of distinguishing the clearly malignant histiocytoses from the remaining subtypes, the so-called “dis-orders of varied biological behavior”. Acute myelomonocytic leukemia (FAB M4), acute monocytic leukemia (FAB M5), chronic myelomonocytic leukemia and the histiocytic sarco-mas are all classified in the malignant histiocytoses category. The disorders of varied biological behavior continued to be divided into dendritic cell-related disorders (class I) and macrophage-related disorders (class II). The dendritic cell-related disorders include Langerhans cell histiocytosis, the most common type in this class, in addition to other less common subtypes. Primary and secondary hemophagocytic lymphohistiocytosis, in addition to sinus histiocytosis with massive lymphadenopathy (also known as Rosai–Dorfman disease), are the two major types of macrophage-related his-tiocytosis discussed in this chapter. This classification schema is summarized in Table 15.1. Table 15.1Classification of histiocytic disorders. Class I: dendritic cell histiocytoses Langerhans cell histiocytosis Secondary dendritic cell processes Juvenile xanthogranuloma and related disorders Erdheim–Chester disease Solitary histiocytomas of various dendritic cell phenotypes Class II: nondendritic cell histiocytoses Primary hemophagocytic lymphohistiocytosis Familial hemophagocytic lymphohistiocytosis Secondary hemophagocytic lymphohistiocytosis Infection associated Malignancy associated Rosai–Dorfman disease (sinus histiocytosis with massive lymphadenopathy) Solitary histiocytoma with macrophage phenotype Class III: malignant histiocytoses Monocyte related Leukemias ( FAB and revised FAB classification) Monocytic leukemia M5A and M5B Acute myelomonocytic leukemias M4 Chronic myelomonocytic leukemias Extramedullary monocytic tumor or sarcoma Dendritic cell-related histiocytic sarcoma Macrophage-related histiocytic sarcoma FAB, French–American–British. In 1973 Nezelof et al. 22 provided definitive evidence for the phenotypic similarity of normal Langerhans cells and LCH cells, including a description of the presence of Birbeck granules in both cell types. However, LCH cells, in contrast to normal Langerhans cells, typically lack dendritic cell exten-sions and have a rounded appearance with distinct cellular margins. These cells express CD1a, S100 and Langerin (CD207) but not the typical markers of more mature dendritic cells such as CD83, CD86 and DC-Lamp (Fig. 15.2). In addition, these cells express CD40 and intracellular MHC class II pro-teins but are inefficient antigen-presenting cells. When LCH cells are exposed in vitro to CD40L they acquire markers of dendritic cell maturation. 23 LCH cells also express CCR6, the receptor for the proinflammatory chemokine CCL20/MIP3α, a characteristic of immature dendritic cells. Furthermore, these cells have been shown to also secrete CCL20/ MIP3α, CCL5/RANTES and CXCL11/I-TAC, all of which are believed to function in recruiting additional LCH cells, eosinophils and T cells to LCH lesions. 12 Of note, the co-expression of CCR6 and CCR7 on LCH cells has also been reported.