Malignant histiocytosis is a rare neoplasm composed of cells with morphological and immunological characteristics similar to those of mature tissue histiocytes. The neoplasm may be disseminated or localized. An aggressive disease, it is often diagnosed at an advanced stage.
There have been many inconsistencies in the naming, classifying, and diagnosing of malignant histiocytosis . The original description of the disease was based on visual inspection and then on light microscopy. Later, as immunological and molecular techniques became available, many cases that were originally diagnosed as malignant histiocytosis were shown to be T cell or B cell lymphomas . Therefore, the 2001 World Health Organization guidelines required the demonstration that there was no T or B cell specific gene rearrangements; however, in the 2008 guideline, this stipulation was abandoned  .
The classification and naming of malignant histiocytosis are also somewhat controversial. The disease has been referred to, among others, as atypical Hodgkin’s disease, histiocytic lymphoma, histiocytic medullary reticulosis , histiocytic sarcoma,  , or true histiocytic lymphoma.
The disease is very rare, and sometimes coexists with B or T cell neoplasms, or appears subsequently. It can present in various organs, mainly the lymph nodes, skin, gastrointestinal tract, and spleen, but many other sites can harbor malignant histiocytosis. Systemic symptoms, such as fever, fatigue, night sweats, and weight loss are often observed. Lymphadenopathy, splenomegaly, hepatomegaly, skin conditions such as rashes and multiple tumors, as well as gastrointestinal and other problems, are also encountered.
The tumor cells are large, oval-shaped or round, with eosinophilic cytoplasm that can look foamy because of elevated lipid levels. The cells do not adhere to each other. Bi- or multinucleated cells are not uncommon, and the nuclei can have multiple lobes. Mitoses and phagocytic activity are often observed. Lysosomes are seen in the cytoplasm in substantial numbers, but not Birbeck granules, which are cytoplasmic inclusions characteristic of Langerhans cells . Various benign immune cells are also present - lymphocytes, neutrophils, eosinophils, and non-malignant histiocytes.
Immunological methods are used extensively for the diagnosis of malignant histiocytosis; a large number of histiocytic and other markers are available. Except for the extremely rare cases of transdifferentiation, an immunological examination should show the reaction with macrophage markers and lack of reaction with markers for myeloid cells, dendritic and Langerhans cells, B cells, T cells, and epithelial cells. Histiocytic markers are CD163 and CD 68, the latter being used regularly, although it is known to react with other types of cancer cells in addition to those of monocytic/macrophage origin . CD163, which is a hemoglobin scavenger receptor, is essentially specific for macrophages or histiocytes . Among other macrophage specific markers are CD11c, CD14, and CD31. No immunochemical staining with myeloid markers (myeloperoxidase, CD33 and CD34), dendritic cell markers (CD1a, CD21 and CD35), or T or B cell markers should be observed    , although, as mentioned above, a few examples of transdifferentiation have been described. Similarly, in most cases, immunoglobulin or T cell receptor gene rearrangements are not detected.
Benign and malignant histiocytes carry similar markers, therefore distinguishing them has to be based on cell morphology. Distinction from Langerhans cell neoplasms is by immunological markers, in addition to an absence of the characteristic Birbeck granules of Langerhans cells. Anaplastic large cell lymphoma, the cells of which are morphologically similar to malignant histiocytes, is most easily mistaken for malignant histiocytosis. However, anaplastic lymphoma cells express CD30, ALK-1, and other markers. Moreover, they harbor a characteristic chromosomal translocation, and T cell receptor gene rearrangements .