CHAPTER 76 CLASSIFICATION AND CLINICAL MANIFESTATIONS OF DISORDERS OF MONOCYTES AND MACROPHAGES
CHAPTER 76 CLASSIFICATION AND CLINICAL MANIFESTATIONS OF DISORDERS OF MONOCYTES AND MACROPHAGES
MARSHALL A. LICHTMAN
Monocytosis and Histiocytosis
Qualitative Disorders of Monocytes
Clinical Manifestations of Monocyte Disorders
Monocytopenia or Monocyte Dysfunction
Disorders that result in abnormalities of monocytes exclusively are uncommon and are referred to as histiocytoses. These disorders may be inherited, such as familial hemophagocytic lymphohistiocytosis; inflammatory, such as infectious hemophagocytic syndrome; neoplastic, such as Langerhans cell histiocytosis; or they may result from exaggerated storage of macromolecules, such as Gaucher’s disease. Some cases of myelogenous leukemia have progenitor cells that mature preferentially into leukemic monocytes. Certain acquired diseases that affect hematopoiesis result in a severe depression of blood monocytes (along with other blood types). Inherited disorders affecting white cells may result in impaired monocyte function, such as Chédiak-Higashi syndrome. Table 76-1 categorizes the qualitative and quantitative abnormalities of monocytes and macrophages.
TABLE 76-1 DISORDERS OF MONOCYTES AND MACROPHAGES
Classification of monocytic disorders is difficult because few abnormalities result solely in a disturbance of monocytes or macrophages. However, the presence of monocytopenia or monocytosis may be an important diagnostic feature or contribute to the functional abnormality in the patient.
The terms histiocyte and macrophage have been 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 histiocytosis and histiocyte continue to be used for diseases that principally involve cells derived from blood monocytes, i.e., macrophages.
It is important that the physician consider the absolute 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 (see Chap. 77).
Table 76-1 contains a classification of monocyte and macrophage disorders.
Two striking examples of disorders accompanied by severe monocytopenia are aplastic anemia and hairy cell leukemia. In both conditions pancytopenia is usual, but the predisposition to serious infection is heightened by the deficiency in monocyte production.
MONOCYTOSIS AND HISTIOCYTOSIS
Monocytosis is often the manifestation of an inflammatory or a neoplastic disease (see Chap. 91). Certain hemopoietic tumors, especially acute and chronic monocytic leukemia, have as their principal manifestation a predominance of monocytic cells in blood and marrow. Occasionally, chronic monocytosis can precede the onset of acute myelogenous leukemia. Dendritic cell variants of acute myelogenous leukemia have also been discovered since immunophenotyping and genotyping of acute leukemias have become frequent.
Histiocytic lymphoma was so named because it was thought to be a tumor of malignant macrophages involving lymph nodes, based on microscopic examination of lymph node cell appearance. Now, as a result of immunophenotyping, it is recognized as a malignancy usually of large T or occasionally B lymphocytes (see Chap. 78). In very infrequent cases the tumors have a histiocytic (macrophagic) phenotype. These cases are referred to as malignant histiocytosis or histiocytic sarcoma (see Chap. 78). In some cases of monocytic leukemia, the malignant clone does not appear to include precursors of red cells and platelets and thus is not likely to be the result of a mutation in the stem cell. Progenitor cell monocytic leukemia and malignant histiocytosis support the concept that primitive monocyte cells, committed to the monocyte-macrophage lineage, can undergo malignant transformation.
Several uncommon types of histiocytoses are serious systemic diseases and may mimic malignant disease; however, the cytopathologic changes in monocytes or macrophages are not indicative of a malignant transformation and are presumably not clonal in origin. Familial and sporadic hemophagocytic lymphohistiocytosis, infection-induced hemophagocytic syndromes, and sinus histiocytosis with massive lymphadenopathy are among such disorders (see Chap. 78).
QUALITATIVE DISORDERS OF MONOCYTES
Inherited abnormalities of macrophages can result in ineffective function of these cells. In these situations the abnormality is usually shared by other cells, as in chronic granulomatous disease, which results from a defect in oxygen-dependent microbial killing, and in Chédiak-Higashi disease, which results from an abnormality of the membranes of cell granules (see Chap. 72). An indomethacin-sensitive monocyte killing defect in children has been associated with a predisposition to atypical mycobacterial disease (see Table 76-1). Also, enzyme deficiencies can result in accumulation of undegraded macromolecules in macrophages, leading to various types of storage diseases. A classic example is Gaucher disease, a disorder that results from deficiency of the enzyme glucocerebrosidase (see Chap. 79).
Acquired functional abnormalities of monocytes have been reported in a variety of diseases and circumstances (see Table 76-1, especially “Monocyte and Macrophage Dysfunction”). For example, the output of prostaglandin E2 is elevated and interleukin-2 synthesis is depressed in monocytes for several weeks after an individual suffers major trauma. Interferon-g synthesis by mitogen-stimulated lymphocytes is depressed concomitantly. These changes may play a role in posttraumatic immunosuppression.
Monocyte dysfunction may also be acquired in patients with solid tumors. This dysfunction is correlated with decreased monocyte expression of HLA-DR antigens and lower than expected production of interleukin-1b and tumor necrosis factor-a.
CLINICAL MANIFESTATIONS OF MONOCYTE DISORDERS
MONOCYTOPENIA OR MONOCYTE DYSFUNCTION
Isolated monocytopenia does not occur. Thus, the manifestations of such a clinical state must be inferred. Neutrophils, endothelial cells, and other cell types can substitute in part for some monocyte functions. Monocytes have antibacterial, antiviral, antifungal, and antiparasitic capabilities. They are effective phagocytes that are involved in the ingestion of organisms such as mycobacteria, Listeria, Brucella, trypanosomes, and other granuloma-producing organisms. Thus, their deficiency or functional abnormality predisposes to such infections. Macrophages can serve as a reservoir for the human immunodeficiency virus and is the principal locus for the virus in brain and neural tissue.
Deficiency in a specific subset of macrophages, the osteoclasts, results in osteopetrosis, an imbalance in bone metabolism that favors accretion; osteoclasts play a key role in bone resorption.
Macrophages process and present antigens and play a role in immune regulation. In complex systems, such as that of antibody production, abnormal macrophages might lead to faulty modulation of antibody synthetic rates. Activated monocytes secrete over 50 chemical mediators or monokines. The absence of monocytes from the inflammatory response and the failure to elaborate or the inappropriate elaboration of monokines such as IL-1, a1-proteinase inhibitor, prostaglandins, leukotrienes, plasminogen activator, elastase, tumor necrosis factor, IL-6, IL-12, and others may cause or contribute to disease manifestations. A deficiency or impairment of monocytes has the potential of influencing several functions and systems because monocytes are such important sources of cytokines.
Monocytopenia and decreased monocyte entry into inflammatory sites occur after glucocorticoid administration. This may explain why patients treated with glucocorticoids are predisposed to infections in which monocytes play a protective role, such as those resulting from fungi, mycobacteria, and other opportunistic organisms. Dysfunctional monocytes, incapable of killing ingested microorganisms, are present in chronic granulomatous disease (see Chap. 72), as well as in hematopoietic stem cell diseases such as acute myelogenous leukemia.
Benign monocytosis is not associated with specific clinical manifestations. All forms of myelogenous leukemia with a predominance of monocytes are associated with a predisposition to troublesome tissue infiltrates, especially in the skin, gingiva, lymph nodes, meninges, and anal canal. The higher the proportion of leukemic monocytes and the higher the monocyte count, the more prevalent is tissue infiltration. Release of procoagulants leading to intravascular coagulation also occurs in myelogenous leukemia with a high proportion of monocytes (see Chap. 93).
This term usually refers to the accumulation of activated macrophages (histiocytes) in tissue sites. The cells may become cytophagocytic; ingestion of red cells and occasionally of leukocytes, platelets, erythroblasts in marrow or cells in other tissue sites is an important feature of certain inflammatory histiocytosis (see Chap. 78). Because morphology has been misleading, the diagnosis of histiocytosis requires identification of specific cell markers. Histiocytoses may be inflammatory (polyclonal) or neoplastic (clonal). Because tissue macrophages can take on highly specialized phenotypes and localize in different tissues, histiocytoses are further defined by whether they carry markers of these cell types (e.g., Langerhans cells, dendritic cells).
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