Deciphering the histiocytic code

Deciphering the histiocytic code

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Dec 01, 2006

Many clinicians cringe when they see the word histiocytic on a diagnostic report. The nomenclature of histiocytic diseases can be difficult to understand, leading to confusion in regards to diagnostic and therapeutic options. To further compound the confusion, it can be easy to misdiagnose these diseases with only routine histopathology. This article is designed to provide a better understanding of the histiocytic diseases, as well as to provide information regarding the diagnosis and clinical presentation of these diseases and available treatment options.

Origin of histiocytes

In order to understand the classification of the histiocytic disorders, a brief review of immunology is needed. Traditionally the term histiocyte has been used to refer only to differentiated cells of the monocyte/macrophage line. However, the current classification scheme includes two cell lines: Langerhans/dendritic cells and the monocyte/ macrophage series. It is believed that these two cell lines arise from a common stem cell in the bone marrow since these cells share certain surface markers, respond to the same growth factors and can produce the same biologically active molecules. However, during the maturation process, the morphology and the function of these two lines become different (Cline 1994).

Macrophages develop from a stem cell known as the colony-forming unit granulocyte-macrophage (CFU-GM). Promonocytes mature into monocytes in the bone marrow, which then are released into the blood stream and enter the tissues to complete the maturation process. These cells are phagocytic, and they protect the body from micro-organisms as well as other organic and inorganic particles through the process of phagocytosis. Langerhans cells develop from a bone marrow stem cell, but the maturation process begins in the epidermis and is completed in T cell-rich areas. When fully mature, these are considered to be Langerhans or dendritic cells. These cells are not poorly phagocytic but function in the immune system as antigen presenting cells (Cline 1994).

Diagnosis of histiocytic diseases

With only routine H&E stains it can be difficult to make an accurate diagnosis of a histiocytic disease. Diseases that have been confused with the histiocytic disorders based on morphologic appearance include lymphomatoid pulmonary granulomatosis, large cell anaplastic carcinoma of the lung and granulomatous inflammatory conditions. There are also diseases that were initially classified to be of histiocytic linage but have since been found to arise from different stem cells (i.e. malignant fibrous histiocytoma). In addition, the term histiocytic has been applied to diseases in which the cells are morphologically similar to histiocytes but are of a different cell linage (i.e. histiocytic lymphoma).

The advent of immunohistochemical markers for histiocytes has led to a more accurate diagnosis and classification of the histiocytic diseases. In most cases, a panel of markers provides more information than only a single marker. Markers that can be used to identify histiocytic cells on formalin-fixed tissue include lysozyme and CD18. Fresh frozen tissue is considered superior to formalin-fixed tissue since it is possible to identify several additional markers (ie.CD1, MHC II). Depending on the differential diagnoses, markers for non-histiocytic cells such as CD3 (T-cells), CD79a (B cells) cytokeratin (carcinomas), immunoglobulin light chains (plasma cells) and toluidine blue (mast cells) are often included in the panel. A pathologist can recommend appropriate stains based on the differentials. Keep in mind that negative markers do not necessarily rule out a specific disease, since more undifferentiated cells may lose these markers.

Classification of histiocytic disorders


Table 1 Histiocytic disorder classifications
Most of the histiocytic disorders can be placed into one of four categories: reactive macrophage histiocytoses, malignant macrophage histiocytoses, reactive Langerhans cell (dendritic) histiocytoses and malignant Langerhans cell (dendritic) histiocytosis. In dogs, the majority of histiocytic diseases have been found to be of Langerhans cell origin, given that they express CD1 on the surface of the cells. The current classification scheme includes both reactive and malignant disease entities (Table 1).