Classification and Clinical Manifestations of Disorders of Monocytes and Macrophages



Disorders that exclusively result in abnormalities of monocytes, macrophages, or dendritic cells are uncommon and usually are referred to, pathologically, as histiocytosis. These disorders can be inherited, such as familial hemophagocytic lymphohistiocytosis; inflammatory, such as infectious hemophagocytic lymphohistiocytic syndrome; or clonal (neoplastic), such as Langerhans cell histiocytosis. They can result from an inherited enzyme insufficiency in macrophages that lead to exaggerated storage of macromolecules, such as in Gaucher disease. Monocytes are critical sources for proinflammatory and inflammatory cytokines and, when inappropriately activated, can result in the lymphohistiocytic hemophagocytic syndrome with fever, intravascular coagulation, and organ pathology. A variety of hematopoietic neoplasms may have a phenotype characterized by a large proportion of monocytes. Idiopathic (clonal) monocytosis is a rare manifestation of a myelodysplastic syndrome. Some cases of myelogenous leukemia have progenitor cells that mature preferentially into leukemic monocytes, including acute monoblastic or monocytic leukemia, chronic myelomonocytic leukemia, and juvenile myelomonocytic leukemia. Two acquired diseases, hairy cell leukemia and aplastic anemia, result in a severe depression of blood monocytes (along with other blood cell types). Mutations in GATA2 are associated with severe monocytopenia and mycobacterial infections (the MonoMAC syndrome). Inherited disorders affecting white cells, such as chronic granulomatous disease and Chédiak-Higashi syndrome, result in impaired monocyte function. Monocyte dysfunction may accompany a variety of severe illnesses, such as sepsis, trauma, and cancer. Monocytes also contribute to a variety of diseases, such as Crohn disease and rheumatoid arthritis, by virtue of their being a principal source of tumor necrosis factor. Monocytes play a pathogenetic role in other complex, acquired disorders, such as thrombosis and atherogenesis. Table 69–1 catalogues the qualitative and quantitative abnormalities of monocytes, macrophages, and dendritic cells.

Table 69–1.   Disorders of Monocytes and Macrophages 

Acronyms and Abbreviations

CD, cluster of differentiation; GM-CSF, granulocyte-macrophage colony-stimulating factor; HLA-DR, human leukocyte antigen-D related; IL, interleukin; MonoMAC, monocytopenia and mycobacterial infections syndrome; TNF, tumor necrosis factor.


Classification of monocytic disorders is difficult because few abnormalities result solely in a disturbance of monocytes or macrophages. However, the presence of monocytopenia, monocytosis, histiocytosis, or qualitative disorders of monocytes may be an important diagnostic feature or contribute to the functional abnormality in the patient.

The terms histiocyte and macrophage are synonymous. The latter term is customary when discussing the biology of the cells of the mononuclear phagocyte system, which is the total pool of marrow, blood, and tissue monocytes and macrophages, formerly referred to as the reticuloendothelial system. In disease nosology, the terms histiocyte and histiocytosis continue to be used for diseases that principally involve cells derived from blood monocytes, that is, macrophages and monocyte-derived dendritic cells.

The physician should consider the absolute monocyte count and not the percent of cells that are monocytes when evaluating the differential blood cell count before concluding that there is an inappropriate content of blood monocytes (Chap. 70).

Table 69–1 lists a classification of monocyte and macrophage disorders of relevance to hematologists.


Table 69–1 contains several important causes of monocytopenia. Two notable examples of disorders accompanied by severe monocytopenia are aplastic anemia and hairy cell leukemia. Pancytopenia is usual in both conditions, but the predisposition to serious infection is heightened by the deficiency in monocyte production. In hairy cell leukemia, the severe monocytopenia represents an important diagnostic clue because of its constancy. A syndrome of profound monocytopenia, often amonocytosis, associated with susceptibility to mycobacterial avian complex, fungal, and disseminated papilloma virus infections, and subsequent development of myelodysplasia or acute myelogenous leukemia in some cases, was first described in 2010 (see Table 69–1). It is accompanied by blood B-cell lymphopenia and decreased circulating and tissue dendritic cells, but not by hypogammaglobulinemia or a deficiency of tissue macrophages or skin Langerhans (dendritic) cells. It is the result of mutations of GATA2 that impair transcription of its mRNA and is usually inherited as an autosomal recessive or can occur sporadically. The mutations of GATA2 were found in germline and hematopoietic tissues, adding it to the familial leukemia genes, as well as to a slow onset (sometimes decades), complex immunodeficiency state.


Table 69–1 contains a comprehensive list of causes of monocytosis. Monocytosis is often the manifestation of an inflammatory or a neoplastic disease. Certain hematopoietic tumors, especially acute monocytic and chronic myelomonocytic leukemia, have as their principal manifestation a predominance of monocytic cells in marrow and blood. Occasionally, chronic monocytosis can precede the onset of acute myelogenous leukemia, representing an uncommon manifestation of the myelodysplastic syndromes. Dendritic cell variants of acute myelogenous leukemia have also been discovered since the advent of immunophenotyping and genotyping of acute leukemias. The precise derivation of these myeloid dendritic cells is uncertain (i.e., granulocytic or monocytic). In some cases of monocytic leukemia, the malignant clone does not appear to include progenitors of red cells and platelets. Such cases are not likely to be the result of a mutation of a multipotential hematopoietic cell. This type of progenitor cell monocytic leukemia and other histiocytic or dendritic cell tumors support the concept that primitive cells, committed to the monocyte-macrophage lineage, can undergo malignant transformation (Chaps. 83 and 88).

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Jun 14, 2016 | Posted by in HEMATOLOGY | Comments Off on Classification and Clinical Manifestations of Disorders of Monocytes and Macrophages
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