Hematopoietic and Lymphatic Tissues

Cells of the hematopoietic and lymphatic tissues serve vital functions of host defense, internal homeostasis, and bodily intactness. They all originate from the same stem cell population and in their functional activities interact in various ways (see chapter 1). Disorders in one cell population may thus cause reactions in the other. For this reason, the hematopoietic and lymphatic systems are discussed together. Just as there are a large number of different cell populations with various differentiation stages and functional activities, so are there a multitude of human diseases of the blood and lymphatic systems. The most common and important are discussed in this chapter. The most common leading symptoms of all these diseases are infection, hemorrhage or thrombosis, and anemia.

Red Blood Cell Disorders

Red blood cell (RBC) disorders manifest themselves by either a decrease (anemia) or an increase (erythrocytosis) of RBCs, the latter being reactive or neoplastic in nature. These disorders preferentially affect oxygen transport to tissues; excessive erythrocytosis may be complicated by increased intravascular thrombosis.

White Blood Cell Disorders (Nonlymphatic)

White blood cell (WBC) disorders (nonlymphatic) include reactive and neoplastic changes of hematopoietic tissues. Reactive changes may be either hyperplastic (leukocytosis) or hypoplastic/aplastic (leukopenia). They arise in response to exogenous or endogenous stimuli and generally are reversible. Neoplastic changes (myelodysplastic or myeloproliferative syndromes, leukemia) also may occur in response to certain stimuli (e.g., carcinogens, radiation, viral infection) but become autonomous and thus practically irreversible.

Nonneoplastic Lymphatic Disorders

Lymphatic tissues are the body’s main carriers of host defense, both specific and nonspecific. Consequently, nonneoplastic changes in the lymphatic system may result from functional alterations in the immune system as well as from inflammatory, necrotic, or metabolic disorders. Changes in lymph nodes or spleen may be secondary to other disorders, as when the lymph system or bloodstream transports disease products from a primary disease focus (e.g., lymphadenitis in the neck developing secondary to a dental abscess or septic splenitis secondary to bacterial enterocolitis). Investigation of a patient with some form of lymphatic disease therefore must always include a search for a primary cause.

Neoplastic Lymphatic Disorders

Malignant neoplasias of the lymphatic tissues are collectively identified as malignant lymphomas (MLs) or, when malignant cells circulate in the blood, lymphocytic leukemias. There are 2 major groups of MLs: Hodgkin lymphomas (lymphogranulomatosis) and non-Hodgkin lymphomas (NHLs). Hodgkin lymphoma, or Hodgkin disease (HD), is distinguished from NHL by its polymorphic features, including certain inflammatory components such as fibrosis and occasional regression simulating nonneoplastic diseases, which eventually may progress to ML. Although it is a lymphatic malignancy, it is accompanied by a large number of associated nonneoplastic cells, which may influence the course and progression of the disease. NHL, by contrast, begins as malignant clonal proliferations. Transition from HD to NHL and combinations of HD with certain types of NHL have been observed (HD and chronic lymphocytic leukemia [CLL] or follicular center cell lymphoma [FCC]; see Table 10-4).

Along with diagnosing an ML as HD or NHL and determining the subclassification based on histologic, immunologic, and cytogenetic markers, staging of disease extent helps to determine the appropriate treatment and the life expectancy of the patient. Staging of all lymphomas is similar: stage I indicates involvement by lymphoma of 1 lymph node site (e.g., axillary, neck); stage II indicates involvement of 2 lymph node sites on the same side of the diaphragm (e.g., neck and axillary, or left and right inguinal); stage III indicates involvement of lymph nodes on both sides of the diaphragm; and stage IV indicates involvement of lymphatic and extralymphatic sites (e.g., liver, spleen, bone marrow). ML may arise from sites other than the lymph nodes. These are grouped together as extranodal lymphomas and have different staging.

TABLE 10-1

CLASSIFICATION OF ANEMIAS*

Category	RBCs	Characteristics
Blood loss, acute	Initially: normochromic, normocytic Later: hypochromic reticulocytosis	Acute volume depletion RBC reduction secondary to fluid influx Rapid RBC regeneration
Blood loss, chronic	Hypochromic	Reduced iron stores
Increased Destruction of Erythrocytes
Hemolytic anemias		Features of hemolysis and tissue siderosis Bone marrow: significant erythropoietic hyperplasia Splenomegaly
Immunologic	Reticulocytosis	Autoantibodies against RBC (infection or drug induced) Isohemagglutinins (transfusion induced, erythroblastosis fetalis)
Mechanical	Schistocytes	Microangiopathic: Hemolytic uremic syndrome Thrombotic thrombocytopenic purpura Trauma by intracardiac artificial devices Multiple hemangiomas (e.g., hepatic)
Hereditary	Spherocytosis Elliptocytosis Sickle cells Hypochromic, microcytic Heinz bodies	RBC membrane and cytoskeleton deficiencies Hemoglobinopathies: sickle cell anemia, thalassemia Enzyme deficiencies (e.g., of hexose monophosphate shunt)
Deficient Erythropoiesis
“Stem cell” defect	Normochromic, Normocytic to mildly macrocytic	Aplastic anemia (with pancytopenia), pure red cell aplasia secondary to myelofibrosis (with thrombocytopenia, splenomegaly)
Maturation defect	Megaloblastic Anisocytic Hypochromic Poikilocytic	Pernicious anemia (vitamin B₁₂ deficiency), folate deficiency, anemia, iron deficiency (infection, tumor, chronic blood loss)
Hb synthesis defect	Sideroblasts	Sideroblastic anemia

normochromic: normal color (i.e. normal Hb content); normocytic: normal size and shape of RBC; hemolytic: red cell lysis

^*Hb indicates hemoglobin; RBC, red blood

TABLE 10-2

REACTIVE HEMATOPOIETIC HYPERPLASIA (NONLYMPHATIC)

Involved Cell Compartment	Cause
Erythrophilic, neutrophilic, and megakaryopoiesis	Blood loss or transient myelotoxic agents
Preferentially neutrophilic	Pyogenic bacterial infections, extensive tissue necroses
Preferentially neutrophilic	Less extensive: drugs such as SCF, steroids
Neutrophilic and histiocytic (frequently with lymphocytes and eventual granuloma formation)	Chronic infections such as by intracellular organisms (e.g., Rickettsia, Yersinia, Salmonella, mycobacteria), mycoses, collagen-vascular diseases (e.g., lupus erythematosus)
Preferentially histiocytic	Protozoal infection (e.g., malaria)
	Suggestive viral infection (hemophagocytic syndrome)
	Phagocytosis defects (infantile septic granulomatosis, Chediak-Higashi syndrome, and others)
	Metabolic (various storage diseases: morbus Gaucher, morbus Niemann-Pick, and others)
Eosinophilic	Allergic diseases
	Parasitic infestations
	Viral infections with immune complex reaction (e.g., Hodgkin disease)
	Treatment with IL-2
Basophilic	Certain allergic diseases (e.g., food allergies)
	Certain endocrine disorders (e.g., myxedema)
	Estrogen treatment

SCF indicates colony stimulating factor; IL, interleukin.

TABLE 10-3

CLASSIFICATION IN SUBTYPES OF ACUTE MYELOPROLIFERATIVE DISEASES*

FAB Class	Subtype Name	Abbreviation	Proportion of Acute Myeloproliferative Diseases (%)
M0	Acute myeloblastic leukemia, stem cell (i.e., minimal differentiation)	AML	3-5
M1	Acute myeloblastic leukemia without maturation	AML	15-20
M2	Acute myeloblastic leukemia with maturation	AML	25-30
M3	Acute promyelocytic leukemia	APL	5-20
M4	Acute myelomonocytic leukemia	AMML	20-30
M5	Acute monoblastic leukemia	AMOL	2-9
M6	Acute erythroleukemia	AEL	3-5
M7	Acute megakaryoblastic leukemia		3-12

FAB indicates French-American-British classification.

^*Acute myeloproliferative diseases are clonal neoplastic disorders of hematopoietic stem cells, the classification of which is determined by their preferential cytologic differentiation.

Adapted from Hoffman R et al. Hematology. Philadelphia: Churchill-Livingstone; 2000.

TABLE 10-4

CLASSIFICATION OF LYMPHOMA (NHL) ENTITIES
Revised European American Lymphoma (REAL) Classification

B-Cell Lymphomas	T-Cell and NK-Cell Lymphomas
Precursor B-Cell Neoplasias	Precursor T-Cell Neoplasia
1. Precursor B-lymphoblastic lymphoma (B-LBL) 2. Precursor B-lymphoblastic leukemia (B-ALL)	1. Precursor T-lymphoblastic lymphoma (T-LBL) 2. Precursor T-lymphoblastic leukemia (T-ALL)
Peripheral B-Cell Neoplasias	Pewripheral T-Cell and NK-Cell Lymphomas
1. B-cell chronic lymphatic leukemia (B-CLL) or prolymphocytic leukemia (B-PLL) 2. Small cell lymphocytic lymphoma 3. Lymphoplasmacytoid lymphoma (LPL) or immunocytoma (IC) 4. Mantle cell lymphoma 5. Follicular center cell lymphoma, follicular pattern (FCCf) • Grade I small cell • Grade II mixed small and large cell • Grade III large cell 6. Follicular center cell lymphoma, small cell, diffuse pattern (FCCd) 7. Marginal zone lymphoma (MZL) • Subtype I extranodal MZL of MALT-type with or without monocytoid cells • Subtype II nodal MZL with or without monocytoid cells 8. Margonal zone lymphoma of the spleen (SLVL) 9. Hairy cell leukemia (HCL) 10. Plasmacytoma/multiple myeloma 11. Diffuse large cell B-cell lymphoma subtype: primary B-cell lymphoma of mediastinum (of thymic origine) 12. Burkitt lymphoma 13. B-cell lymphoma of high malignancy of Burkitt type	1. T-cell chronic lymphatic leukemia (T-CLL) or T-cell prolymphocytic leukemia (T-PLL) 2. Large granular cell lymphocytic leukemia (LGL) • Suptype: T-cell type • Subtype: NK-cell type 3. Mycosis fungoides/Sezary’s syndrome (MF/SS) 4. Peripheral T-cell lymphoma NOS (not otherwise specified) • Subtype: Subcutaneous panniculitic T-cell lymphoma • Subtype: Hepatosplenomegalic gamma/delta T-cell lymphoma 5. Angioimmunoblastic T-cell lymphoma (AILD) 6. Angiocentric lymphoma 7. Intestinal T-cell lymphoma 8. Adult T-cell lymphoma/leukemia (ATL/L) 9. Anablastic large cell lymphoma (ALCL), CD30+, T- or 0-Cell Type 10. Anablastic large cell lymphoma, Hodgkin-like