diseases of white blood cells

Diseases of White Blood Cells

Lecturer :Yiran Ni, MD

Department of Pathology

China Three Gorges University

Email:nyr1986@gmail.com

Dec.2012

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.

categories

• 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.

categories

In the following lessons, we will first describe the 1\leukopenic states and summarize the common 2\reactive disorders and then consider in some detail 3\malignant proliferations of white cells.

Target of this class

• Leukopenia;

• Reactive leukocytosis;

• Lymphadenitis;

• General aspects and classification of neoplastic proliferation of white cell;

• Acute myeloid leukaemia

Target of the next 2 class

• chronic myeloid leukaemia

• Lymphoma/lymphoid leukaemia

• splenomegaly

• histiocytoses

• Review the slices we have learned

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).

Leukopenia• Lymphopenia is less common; in addition to

congenital immunodeficiency diseases, 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.

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.

Pathogenesis.

• (1) Inadequate or ineffective granulopoiesis is observed in the setting of:

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

• in these conditions, granulocytopenia is accompanied by anemia and thrombocytopenia.

Pathogenesis.• 2. Suppression of committed granulocytic precursors

due to exposure to certain drugs. • Drugs are responsible for most of the significant

neutropenias . 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

Pathogenesis.

• 3. Disease states associated with ineffective granulopoiesis, such as megaloblastic anemias due to vitamin B12 or folate deficiency and myelodysplastic syndromes, where defective precursors are susceptible to death in the marrow.

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

Pathogenesis.

• (2) Accelerated removal or destruction of neutrophils occurs with

• 1. 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.

Pathogenesis.

• 2. 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.

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

Morphology• Bone marrow:• 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 hypercellularhypercellular owing to the presence of increased numbers of granulocytic precursors.

MorphologyBone marrow:•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.

MorphologyOther organ:•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 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.

MorphologyOther organ:•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 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.

Clinical Course

• 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, broad-spectrum antibiotics are given expeditiously whenever signs or symptoms appear.

Clinical Course

• 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

Reactive Proliferations of White Cells

• Definition: Leukocytosis refers to an increase in the number of blood leukocytes.

• It is a common reaction to a variety of inflammatory states and is sometimes the first indication of neoplastic growth of leukocytes

Pathogenesis

• The peripheral blood leukocyte count is influenced by several factors, including:

• 1. The size of the myeloid (for granulocytes and monocytes) and lymphoid (for lymphocytes) precursor and storage cell pools in the bone marrow, circulation, and peripheral tissues.

Pathogenesis

• 2. The rate of release of cells from the storage pool into the circulation

• 3. The proportion of cells that are adherent to blood vessel walls at any time

• 4. The rate of extravasation of cells from the blood into tissues

Pathogenesis

• leukocyte homeostasis is maintained by cytokines, growth factors, and adhesion molecules through their effects on the commitment, proliferation, differentiation, and extravasation of leukocytes and their progenitors.

Pathogenesis

• In acute infection, there is a rapid increase in the egress of mature granulocytes from the bone marrow pool.

• The release of IL-1, TNF, and other inflammatory cytokines stimulates bone marrow stromal cells and T cells to produce increased amounts of colony-stimulating factors (CSFs), which enhance the proliferation and differentiation of committed granulocytic progenitors and, over several days, cause a sustained increase in neutrophil production

Pathogenesis

• Other growth factors preferentially stimulate other types of leukocytosis.

• For example, IL-5 causes eosinophilia by enhancing the growth, survival, and differentiation of eosinophils, while IL-7 plays a central role in lymphopoiesis.

• Such factors are differentially produced in response to various pathogenic stimuli

Causes of LeukocytosisNeutrophilic leukocytosis

Acute bacterial infections, especially those caused by pyogenic organisms; sterile inflammation(myocardial infarction, burns)

Eosinophilic leukocytosis (eosinophilia)

Allergic disorders such as asthma, allergic skin diseases; parasitic infestations; drug reactions; certain malignancies (e.g., Hodgkin disease and some non-Hodgkin lymphomas); collagen vascular disorders and some vasculitides; atheroembolic disease

Basophilic leukocytosis (basophilia)

Rare, often indicative of a myeloproliferative disease (e.g., chronic myelogenous leukemia)

Monocytosis Chronic infections (e.g., tuberculosis), bacterial endocarditis and malaria; collagen vascular diseases (e.g., systemic lupus erythematosus) and inflammatory bowel diseases (e.g., ulcerative colitis)

Lymphocytosis Accompanies monocytosis in many disorders associated with chronic immunologic stimulation (e.g., tuberculosis); viral infections (e.g., hepatitis)

• In most instances, it is not difficult to distinguish reactive leukocytosis from leukocytosis caused by flooding of the peripheral blood by neoplastic white blood cells (leukemia).

• Uncertainties may arise in two settings:• 1. Particularly in children, acute viral infections can

produce the appearance of activated lymphocytes in the peripheral blood and marrow that resemble neoplastic lymphoid cells.

Pathogenesis

• 2. At other times, particularly in inflammatory states and severe chronic infections, many immature granulocytes appear in the blood, simulating a picture of myelogenous leukemia (leukemoid reaction).

• Special laboratory studies (discussed later) are helpful in distinguishing reactive and neoplastic leukocytoses.

Pathogenesis

Reactive Proliferations of Lymph Nodes

• In addition to causing leukocytosis, infections and inflammatory stimuli often elicit immune reactions within lymph nodes.

• The infections that lead to lymphadenitis are numerous.

• Most cause stereotypic patterns of lymph node reaction designated acute and chronic nonspecific lymphadenitis

Acute nonspecific lymphadenitis

• Lymph nodes undergo reactive changes whenever they are challenged by microbiologic agents, cell debris, or foreign matter introduced into wounds or into the circulation. Acute lymphadenitis is most often seen:

• 1. in the cervical region due to microbial drainage from infections of the teeth or tonsils

Acute nonspecific lymphadenitis

• 2. in the axillary or inguinal regions secondary to infections in the extremities

• 3. mesenteric lymph nodes draining acute appendicitis.

• 4. Systemic viral infections (particularly in children) and bacteremia often produce generalized lymphadenopathy.

Morphology

• Macroscopically, the nodes become swollen, gray-red, and engorged.

• Histologically, there is prominence of the lymphoid follicles, with large germinal centers containing numerous mitotic figures.

• Macrophages often contain particulate debris of bacterial origin or derived from necrotic cells.

Morphology• When pyogenic organisms are the cause of the reaction,

the centers of the follicles may undergo necrosis, the entire node can sometimes be converted into a suppurative mass.

• With less severe reactions, there is a neutrophilic infiltrate about the follicles, and numerous neutrophils can be found within the lymphoid sinuses. The cells lining the sinuses become hypertrophied and cuboidal and often undergo hyperplasia.

Clinical appearence

• nodes with acute lymphadenitis are enlarged because of the cellular infiltration and edema.

• As a consequence of the distention of the capsule, they are tender to touch. When abscess formation is extensive, they become fluctuant.

• The overlying skin is frequently red, and sometimes penetration of the infection to the skin surface produces draining sinuses, particularly when the nodes have undergone suppurative necrosis. As might be expected, healing of such lesions is associated with scarring.

Chronic nonspecific lymphadenitis

• lymph nodes in chronic reactions are not tender, because their capsules are not under increased tension.

• Chronic lymphadenitis is particularly common in inguinal and axillary nodes, which drain relatively large areas of the body and are frequently challenged.

Neoplastic Proliferations of White Cells

• Malignant proliferative diseases constitute the most important disorders of white cells.

• These diseases can be classified into several categories:

• 1. Lymphoid neoplasms

• 2. Myeloid neoplasms

• 3. histiocytoses

Categories

• Myeloid neoplasms arise from hematopoietic stem cells that give rise to cells of the myeloid (i.e., erythroid, granulocytic, and/or thrombocytic) lineage. Three categories of myeloid neoplasia are recognized: 1. acute myelogenous leukemias, in which immature progenitor cells accumulate in the bone marrow; 2. myelodysplastic syndromes, which are associated with ineffective hematopoiesis and resultant peripheral blood cytopenias; and 3. chronic myeloproliferative disorders, in which increased production of one or more terminally differentiated myeloid elements usually leads to elevated peripheral blood counts.

Categories

• Lymphoid neoplasms encompass a diverse group of entities. In many but not all instances, the phenotype of the neoplastic cell closely resembles that of a particular stage of normal lymphocyte differentiation, a feature that is used in the diagnosis and classification of these disorders.

Categories• The histiocytoses are uncommon proliferative lesions of

macrophages and dendritic cells. • "histiocyte" is often applied to cells of macrophage or

dendritic-cell lineage.• A special category of immature dendritic cells referred to

as Langerhans cells gives rise to a spectrum of neoplastic disorders, some of which behave as disseminated malignant tumors, and others as localized benign proliferations. This group is called Langerhans cell histiocytoses.

Etiology and pathogenesis

1. Chromosomal translocations and oncogenes. Nonrandom chromosomal abnormalities, most commonly translocations, are present in the majority of white cell neoplasms. Many specific rearrangements are associated with particular neoplasms, suggesting a critical role in their genesis.

Etiology and pathogenesis

• Chromosomal translocations frequently occur in myeloid neoplasms

Etiology and pathogenesis

• 2. Inherited genetic factors ： individuals with genetic diseases that promote genomic instability.

• telangiectasia, are at increased risk for development of acute leukemia. In addition, both Down syndrome (trisomy 21) and neurofibromatosis type I are associated with an increased incidence of childhood leukemia.

Etiology and pathogenesis

3. Viruses.

Three viruses-human T-cell leukemia virus-1 (HTLV-1), Epstein-Barr virus (EBV), and Kaposi sarcoma herpesvirus/human herpesvirus-8 (KSHV/HHV-8) have been implicated as causative agents.

Etiology and pathogenesis

• HTLV-1 has been associated only with adult T-cell leukemia/lymphoma.

• EBV genomes are found in the tumor cells of a subset of Burkitt lymphoma, 30% to 40% of cases of Hodgkin lymphoma, many B-cell lymphomas occurring in the setting of T-cell immunodeficiency, and rare natural killer cell lymphomas.

• KSHV is uniquely associated with an unusual type of B-cell lymphoma that presents as a malignant effusion, often in the pleural cavity.

Etiology and pathogenesis

• 4. Environmental agents.

• The most clear-cut associations are those of Helicobacter pylori infection with gastric B-cell lymphoma and gluten-sensitive enteropathy with intestinal T-cell lymphoma.

Etiology and pathogenesis• 5. Iatrogenic factors. • Radiotherapy and certain forms of chemotherapy

used to treat cancer increase the risk of subsequent myeloid and lymphoid neoplasms.

• This association is believed to stem from mutagenic effects of ionizing radiation and chemotherapeutic drugs on hematolymphoid progenitor cells.

Myeloid neoplasm

• The common feature that unites this heterogeneous group of neoplasms is an origin from hematopoietic progenitor cells capable of giving rise to terminally differentiated cells of the myeloid series (erythrocytes, granulocytes, monocytes, and platelets).

categories

• Acute myelogenous leukemias, characterized by the accumulation of immature myeloid forms in the bone marrow and the suppression of normal hematopoiesis

• Myelodysplastic syndromes, associated with ineffective hematopoiesis and associated cytopenias

• Chronic myeloproliferative disorders, usually associated with an increased production of terminally differentiated myeloid cells

Acute myelogenous leukemias

• Acute myelogenous leukemias affect primarily adults, peaking in incidence between the ages of 15 and 39 years, but are also observed in older adults and children.

• AML is quite heterogeneous, reflecting the complexities of myeloid cell differentiation

Pathophysiology

• Most AMLs are associated with acquired genetic alterations that inhibit terminal myeloid differentiation. As a result, normal marrow elements are replaced by relatively undifferentiated blasts exhibiting one or more types of early myeloid differentiation.

• The replication rate of these blasts is actually lower than that of normal myeloid progenitors, highlighting the pathogenic importance of blocked maturation and increased survival.

Pathophysiology

• In all AMLs, the accumulation of proliferating neoplastic myeloid precursor cells in the marrow suppresses remaining normal hematopoietic progenitor cells by physical replacement as well as by other unknown mechanisms.

• The failure of normal hematopoiesis results in anemia, neutropenia, and thrombocytopenia, which cause most of the major clinical complications of AML.

Pathophysiology

• Therapeutically, the aim is to clear the bone marrow of the leukemic clone, thus permitting resumption of normal hematopoiesis. This can be accomplished by treatment with cytotoxic drugs or, in the specific case of acute promyelocytic leukemia, by overcoming the block in differentiation with pharmacologic doses of retinoic acid.

Chromosomal Abnormalities

• Particular chromosomal abnormalities correlate with the clinical setting in which the tumor occurs. AML arising de novo in patients with no risk factors are often associated with balanced chromosomal translocations, particularly t(8;21), inv(16), and t(15;17).

Chromosomal Abnormalities

• In contrast, AMLs following myelodysplastic syndromes or exposure to DNA-damaging agents (such as chemotherapy or radiation therapy) are commonly associated with deletions or monosomies involving chromosomes 5 and 7 and usually lack chromosomal translocations.

Classification• In the most widely used system in current use, the revised

FAB, AML is divided into eight (M0 to M7) categories.• This scheme takes into account both the degree of

maturation (M0 to M3) and the lineage of the leukemic blasts (M4 to M7).

• Histochemical stains for peroxidase, specific esterase, and nonspecific esterase, and immunostains for myeloid specific antigens play important roles in defining the type of myeloid differentiation that blasts exhibit.

French-American-British (FAB) Classification of AML FAB

subtype NameApproximate % of

adult patients Prognosis

M0 Undifferentiated acute myeloblastic leukemia

5% Worse

M1 Acute myeloblastic leukemia with minimal

maturation

15% Average

M2 Acute myeloblastic leukemia with maturation

25% Better

M3 Acute promyelocytic leukemia

10% Best

M4 Acute myelomonocytic leukemia

20% Average

M4 eos Acute myelomonocytic leukemia with eosinophilia

5% Better

M5 Monocytic leukemia 10% Average

M6 Acute erythroid leukemia 5% Worse

M7 Acute megakaryoblastic leukemia

5% Worse

Morphology

• The diagnosis of AML is based on finding that myeloid blasts make up more than 20% of the cells in the marrow

Diffuse replacement of normal haematopoiesis in bone Diffuse replacement of normal haematopoiesis in bone marrow by leukemic cellsmarrow by leukemic cells

Morphology

• Myeloblasts have :• delicate nuclear chromatin.• two to four nucleoli.• and more voluminous cytoplasm than

Lymphoblasts.• The cytoplasm often contains fine,

azurophilic ,peroxidase-positive granules.

Morphology

• Distinctive red-staining peroxidase-positive structures called Auer rods, which represent abnormal azurophilic granules, are present in many cases and are particularly numerous in acute promyelocytic leukemia.

• The presence of Auer rods is taken to be definitive evidence of myeloid differentiation.

Morphology

• Monoblasts often have folded or lobulated nuclei, lack Auer rods, and are peroxidase negative and nonspecific esterase positive.

• In some AMLs, blasts exhibit megakaryocytic differentiation, which is often accompanied by marrow fibrosis caused by the release of fibrogenic cytokines.

• Rarely, the blasts of AML show evidence of erythroid differentiation (erythroblasts)..

Morphology

• The number of leukemic cells in the peripheral blood is highly variable. Blast counts can be more than 100,000 cells per microliter but are under 10,000 cells per microliter in about 50% of the patients.

• Occasionally, the peripheral smear might not contain any blasts (aleukemic leukemia). For this reason, bone marrow examination is essential to exclude acute leukemia in pancytopenic patients.

Acute myelogenous

leukemia (FAB M1 subtype).

• Myeloblasts have delicate nuclear chromatin, prominent nucleoli, and fine azurophilic granules in the cytoplasm

Acute promyelocytic

leukemia (FAB M3 subtype).

• Bone marrow aspirate shows neoplastic promyelocytes with abnormally coarse and numerous azurophilic granules. Other characteristic findings include the presence of several cells with bilobed nuclei and a cell in the center of the field that contains multiple needlelike Auer rods

Acute monocytic leukemia

(FAB M5b subtype).

• Peripheral smear shows one monoblast and five promonocytes with folded nuclear membranes

Clinical Features

• Most patients present within weeks or a few months of the onset of symptoms related to anemia, neutropenia, and thromobocytopenia, most notably fatigue, fever, and spontaneous mucosal and cutaneous bleeding.

•

Clinical Features

• Often, the bleeding diathesis caused by thrombocytopenia is the most striking clinical feature. Cutaneous petechiae and ecchymoses, serosal hemorrhages into the linings of the body cavities and viscera, and mucosal hemorrhages into the gingivae and urinary tract are common. Procoagulants and fibrinolytic factors released by leukemic cells, especially in acute promyelocytic leukemia (M3), exacerbate the bleeding diathesis.

Cutaneous petechiae and ecchymoses

Clinical Features

• Infections are frequent, particularly in the oral cavity, skin, lungs, kidneys, urinary bladder, and colon, and are often caused by opportunists such as fungi, Pseudomonas, and commensals.

Clinical Features

• Signs and symptoms related to infiltration of tissues are usually less striking in AML.

• Mild lymphadenopathy and organomegaly can occur. In tumors with monocytic differentiation (M4 and M5), infiltration of the skin (leukemia cutis) and the gingiva can be observed, likely reflecting the normal tendency of non-neoplastic monocytes to extravasate into tissues

Clinical Features

• Central nervous system spread is less common than in ALL but still seen.

• Quite uncommonly, patients present with localized masses composed of myeloblasts in the absence of marrow or peripheral blood involvement. These tumors, known variously as myeloblastomas, granulocytic sarcomas, or chloromas, inevitably progress to systemic AML over a period of up to several years.

Prognosis

• AML is a difficult disease to treat.

• Approximately 60% of the patients achieve complete remission with chemotherapy, but only 15% to 30% remain free from disease for 5 years.

• AMLs associated with t(8;21) or inv(16) have a relatively good prognosis with conventional chemotherapy.

Prognosis

• In contrast, the prognosis is dismal for patients with AML with prior myelodysplastic syndrome or following genotoxic therapy, possibly because of damage to normal hematopoietic stem cells. These "high-risk" forms of AML, as well as relapsed AML of all types, are increasingly being treated with allogeneic bone marrow transplantation.

Question of this class

• What is Auer rods?

• Describe the Revised FAB Classification?

• Which type of AML usually associated with the t(8;21)? t(15;17)? inv(16)?

Website for reviewing the slices

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