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CHAPTER 69 CLASSIFICATION

CLASSIFICATION AND Classification of monocytic disorders is difficult because few abnor-
malities result solely in a disturbance of monocytes or macrophages.
CLINICAL MANIFESTATIONS 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.
OF DISORDERS OF term is customary when discussing the biology of the cells of the mono-
The terms histiocyte and macrophage are synonymous. The latter
MONOCYTES AND nuclear phagocyte system, which is the total pool of marrow, blood, and
tissue monocytes and macrophages, formerly referred to as the reticu-
loendothelial system. In disease nosology, the terms histiocyte and his-
MACROPHAGES tiocytosis 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
Marshall A. Lichtman not the percent of cells that are monocytes when evaluating the differ-
ential blood cell count before concluding that there is an inappropriate
content of blood monocytes (Chap. 70).
SUMMARY Table 69–1 lists a classification of monocyte and macrophage dis-
orders of relevance to hematologists.
Disorders that exclusively result in abnormalities of monocytes, macrophages,
or dendritic cells are uncommon and usually are referred to, pathologically, as MONOCYTOPENIA
histiocytosis. These disorders can be inherited, such as familial hemophago- Table 69–1 contains several important causes of monocytopenia. Two
cytic lymphohistiocytosis; inflammatory, such as infectious hemophagocytic notable examples of disorders accompanied by severe monocytopenia
lymphohistiocytic syndrome; or clonal (neoplastic), such as Langerhans cell are aplastic anemia and hairy cell leukemia. Pancytopenia is usual in
histiocytosis. They can result from an inherited enzyme insufficiency in macro- both conditions, but the predisposition to serious infection is height-
phages that lead to exaggerated storage of macromolecules, such as in Gaucher ened by the deficiency in monocyte production. In hairy cell leukemia,
disease. Monocytes are critical sources for proinflammatory and inflammatory the severe monocytopenia represents an important diagnostic clue
cytokines and, when inappropriately activated, can result in the lymphohisti- because of its constancy. A syndrome of profound monocytopenia,
often amonocytosis, associated with susceptibility to mycobacterial
ocytic hemophagocytic syndrome with fever, intravascular coagulation, and avian complex, fungal, and disseminated papilloma virus infections,
organ pathology. A variety of hematopoietic neoplasms may have a phenotype and subsequent development of myelodysplasia or acute myelogenous
characterized by a large proportion of monocytes. Idiopathic (clonal) mono- leukemia in some cases, was first described in 2010 (see Table 69–1). It
cytosis is a rare manifestation of a myelodysplastic syndrome. Some cases of is accompanied by blood B-cell lymphopenia and decreased circulating
myelogenous leukemia have progenitor cells that mature preferentially into and tissue dendritic cells, but not by hypogammaglobulinemia or a defi-
leukemic monocytes, including acute monoblastic or monocytic leukemia, ciency of tissue macrophages or skin Langerhans (dendritic) cells. It is
chronic myelomonocytic leukemia, and juvenile myelomonocytic leukemia. the result of mutations of GATA2 that impair transcription of its mRNA
Two acquired diseases, hairy cell leukemia and aplastic anemia, result in a and is usually inherited as an autosomal recessive or can occur sporadi-
severe depression of blood monocytes (along with other blood cell types). cally. The mutations of GATA2 were found in germline and hematopoi-
Mutations in GATA2 are associated with severe monocytopenia and mycobac- etic tissues, adding it to the familial leukemia genes, as well as to a slow
terial infections (the MonoMAC syndrome). Inherited disorders affecting white onset (sometimes decades), complex immunodeficiency state.
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 MONOCYTOSIS AND HISTIOCYTOSIS
also contribute to a variety of diseases, such as Crohn disease and rheumatoid Table 69–1 contains a comprehensive list of causes of monocytosis.
arthritis, by virtue of their being a principal source of tumor necrosis factor. Monocytosis is often the manifestation of an inflammatory or a neo-
Monocytes play a pathogenetic role in other complex, acquired disorders, such plastic disease. Certain hematopoietic tumors, especially acute mono-
as thrombosis and atherogenesis. Table 69–1 catalogues the qualitative and cytic and chronic myelomonocytic leukemia, have as their principal
manifestation a predominance of monocytic cells in marrow and blood.
quantitative abnormalities of monocytes, macrophages, and dendritic cells.
Occasionally, chronic monocytosis can precede the onset of acute mye-
logenous leukemia, representing an uncommon manifestation of the
myelodysplastic syndromes. Dendritic cell variants of acute myeloge-
nous leukemia have also been discovered since the advent of immuno-
phenotyping and genotyping of acute leukemias. The precise derivation
of these myeloid dendritic cells is uncertain (i.e., granulocytic or mono-
Acronyms and Abbreviations: CD, cluster of differentiation; GM-CSF, cytic). In some cases of monocytic leukemia, the malignant clone does
granulocyte-macrophage colony-stimulating factor; HLA-DR, human not appear to include progenitors of red cells and platelets. Such cases
leukocyte antigen-D related; IL, interleukin; MonoMAC, monocytopenia and are not likely to be the result of a mutation of a multipotential hemato-
mycobacterial infections syndrome; TNF, tumor necrosis factor. poietic cell. This type of progenitor cell monocytic leukemia and other
histiocytic or dendritic cell tumors support the concept that primitive

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