NEUTROPENIA, AGRANULOCYTOSIS

Chapter 14 - Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus

Jon C. Aster MD, PhD

White Blood Cells and Lymph Nodes

Normal

The origin and differentiation of white blood cells (granulocytes, monocytes, and lymphocytes) were briefly discussed in Chapter 13 . Lymphocytes and monocytes not only circulate in the

blood and lymph but also accumulate in discrete, organized masses within lymph nodes, thymus, spleen, tonsils, adenoids, and Peyer patches. Less discrete collections of lymphoid cells

occur in the bone marrow, lungs, gastrointestinal tract, and other tissues. Lymph nodes are the most widely distributed and easily accessible component of the lymphoid tissue and hence

are frequently examined for diagnosis of lymphoreticular disorders. Before discussing these pathologic states, we will briefly review the normal morphology of lymph nodes (shown in Fig.

6-3 , Chapter 6).

Lymph nodes are discrete structures surrounded by a capsule composed of connective tissue and a few elastic fibrils. The capsule is perforated by multiple afferent lymphatics that empty

into a fenestrated subcapsular peripheral sinus. Lymph extravasates from this sinus and slowly percolates through the node, eventually collecting in medullary sinusoids and exiting through

a single efferent lymphatic vessel in the hilus, which is the point of penetration by a single small artery and vein. Situated in the cortex subjacent to the peripheral sinus are spherical or eggshaped

aggregates of small lymphocytes, the so-called primary follicles, which contain numerous immunologically naïve B cells. The paracortical region lying between primary follicles is

populated by numerous evenly dispersed small T lymphocytes. Deep to the cortex lies the medulla, which contains variable numbers of plasma cells and relatively few lymphocytes.

This morphologic description reflects the static organization of a lymph node that is not responding to a foreign invader. As secondary lines of defense, lymph nodes constantly respond to

stimuli, particularly infectious microbes, even in the absence of clinical disease. Within several days of antigenic stimulation, primary follicles enlarge and are transformed into palestaining

germinal centers, highly dynamic structures in which B cells acquire the capacity to make high-affinity antibodies against specific antigens. Normal germinal centers are surrounded by a

dark-staining mantle zone, which contains mainly small naïve B cells. In some reactive conditions, a rim of B cells with slightly more cytoplasm accumulates outside of the mantle zone;

cells occupying this region are called marginal zone B cells. The paracortical T-cell zones also frequently undergo hyperplasia in immune reactions in which cellular immunity is

particularly important, such as viral infections.

The degree and pattern of morphologic change are dependent on the inciting stimulus and the intensity of the immune response. Trivial injuries and infections induce subtle changes in

lymph node histology, while more significant infections inevitably produce enlargement of nodes and sometimes leave residual scarring. For this reason, lymph nodes in adults are almost

never "normal" or "resting," and it is often necessary to distinguish morphologic changes secondary to past experience from those related to present disease.

Pathology

Disorders of white blood cells can be classified into two broad categories: proliferative disorders, in which there is an expansion of leukocytes, and leukopenias, which are defined as a

deficiency of leukocytes. Proliferations of white cells can be reactive or neoplastic. Since the major function of leukocytes is host defense, reactive proliferation in response to an

underlying primary, often microbial, disease is fairly common. Neoplastic disorders, although less frequent, are much more important clinically. In the following discussion, we shall first

describe the leukopenic states and summarize the common reactive disorders and then consider in some detail malignant proliferations of white cells.

Leukopenia

The number of circulating white cells may be markedly decreased in a variety of disorders. An abnormally low white cell count (leukopenia) usually results from reduced numbers of

neutrophils (neutropenia, granulocytopenia). Lymphopenia is less common; in addition to congenital immunodeficiency diseases (see Chapter 6 ), it is most commonly observed in specific

settings, such as advanced HIV infection, following therapy with glucocorticoids or cytotoxic drugs, autoimmune disorders, malnutrition, and certain acute viral infections. Only the more

common leukopenias involving granulocytes will be discussed further here.

NEUTROPENIA, AGRANULOCYTOSIS

Reduction in the number of granulocytes in the peripheral blood (neutropenia) can be seen in a wide variety of circumstances. A marked reduction in neutrophil count, referred to as

arganulocytosis, has serious consequences by making individuals susceptible to infections.

Pathogenesis.

A reduction in circulating granulocytes will occur if there is (1) reduced or ineffective production of neutrophils or (2) accelerated removal of neutrophils from the circulating blood.

Inadequate or ineffective granulopoiesis is observed in the setting of:

• Suppression of myeloid stem cells, as occurs in aplastic anemia (see Chapter 13 ) and a variety of infiltrative marrow disorders (tumors, granulomatous disease, etc.); in these

conditions, granulocytopenia is accompanied by anemia and thrombocytopenia.

• Suppression of committed granulocytic precursors due to exposure to certain drugs, as discussed below.

• Disease states associated with ineffective granulopoiesis, such as megaloblastic anemias due to vitamin B12 or folate deficiency (see Chapter 13 ) and myelodysplastic syndromes,

where defective precursors are susceptible to death in the marrow.

• Rare inherited conditions (such as Kostmann syndrome) in which genetic defects in specific genes result in impaired granulocytic differentiation.

Accelerated removal or destruction of neutrophils occurs with:

• Immunologically mediated injury to the neutrophils, which may be idiopathic, associated with a well-defined immunologic disorder (e.g., systemic lupus erythematosus), or

produced by exposure to drugs.

• Splenic sequestration, in which excessive destruction occurs secondary to enlargement of the spleen, usually associated with increased destruction of red cells and platelets as

well.

• Increased peripheral utilization, as may occur in overwhelming bacterial, fungal, or rickettsial infections.

Drugs are responsible for most of the significant neutropenias (agranulocytoses). Certain drugs, such as alkylating agents and antimetabolites used in cancer treatment, produce

agranulocytosis in a predictable, dose-related fashion. Because such drugs cause a generalized suppression of the bone marrow, production of erythrocytes and platelets is also affected.

Agranulocytosis can also occur as an idiosyncratic reaction to a large variety of agents. The roster of implicated drugs includes aminopyrine, chloramphenicol, sulfonamides,

chlorpromazine, thiouracil, and phenylbutazone. The neutropenia induced by chlorpromazine and related phenothiazines may result from a toxic effect on granulocytic precursors in the

bone marrow. In contrast, agranulocytosis following administration of aminopyrine, thiouracil, and certain sulfonamides likely stems from immunologically mediated destruction of mature

neutrophils through mechanisms similar to those involved in drug-induced hemolytic anemias (see Chapter 13 ).

In some patients with acquired idiopathic neutropenia, autoantibodies directed against neutrophil-specific antigens are detected.[1] Severe neutropenia can also occur in association with

monoclonal proliferations of large granular lymphocytes (so-called LGL leukemia).[2] The mechanism of this neutropenia is not clear; suppression of marrow granulocytic progenitors is

considered most likely.

Morphology.

The anatomic alterations in the bone marrow vary according to the underlying cause. When neutropenia is caused by excessive destruction of mature neutrophils, the marrow is usually

hypercellular owing to the presence of increased numbers of granulocytic precursors. Hypercellularity is also the rule in neutropenias associated with ineffective granulopoiesis, as occurs

in megaloblastic anemias and myelodysplastic syndromes. Agranulocytosis caused by agents that suppress or destroy granulocytic precursors is understandably associated with marrow

hypocellularity.

Infections (most often bacterial or fungal) are a common consequence of agranulocytosis.Ulcerating necrotizing lesions of the gingiva, floor of the mouth, buccal mucosa, pharynx, or

anywhere within the oral cavity (agranulocytic angina) are quite characteristic. These ulcers are typically deep, undermined, and covered by gray to green-black necrotic membranes from

which numerous bacteria or fungi can be isolated. Less frequently, similar ulcerative lesions occur in the skin, vagina, anus, or gastrointestinal tract. Severe life-threatening invasive

bacterial or fungal infections can occur in the lungs, urinary tract, and kidneys. The neutropenic patient is at particularly high risk for deep fungal infections caused by organisms such as

Candida and Aspergillus. Sites of infection often show a massive growth of organisms with little leukocytic response. In the most dramatic instances, bacteria grow in colonies

(botryomycosis) resembling those seen on nutrient media. The regional lymph nodes draining these infections are enlarged and inflamed.

Clinical Course.

The symptoms and signs of neutropenias are related to bacterial or fungal infections. They include malaise, chills, and fever, followed in sequence by marked weakness and fatigability. In

severe agranulocytosis with virtual absence of neutrophils, these infections can be overwhelming and cause death within a few days.

A neutrophil count of less than 1000 cells per mm3 of blood is worrisome, but most serious infections occur with counts below 500 per mm3 . Because infections are often fulminant, broadspectrum

antibiotics are given expeditiously whenever signs or symptoms appear. In some instances, such as following myelosuppressive chemotherapy, neutropenia is treated with

granulocyte colony-stimulating factor (G-CSF), a growth factor that stimulates the production of granulocytes from marrow precursors.

Date: 2016-04-22; view: 905