[04.12a] Pathology of White Blood Cell Disorders V2.pdf

Proliferative disorders and Leukopenia

What are the two broad categories of white blood cell disorders?

Expansion of leukocytes

What characterizes proliferative disorders?

Deficiency of leukocytes

What characterizes leukopenia?

Reactive

What type of white blood cell proliferation is common in infections and inflammatory processes?

Neoplastic

What type of white blood cell proliferation is less frequent but more clinically important?

Complete Blood Count (CBC)

What includes the differential count of white blood cells?

4.8-10.8 x 10³ per microliter

What is the adult reference range for white cells (times 10 to the 3rd power per microliter)?

40-70 percent

What is the adult reference range for Granulocytes (in percent)?

1.2-3.4 times 10 to the 3rd power per microliter

What is the adult reference range for Lymphocytes (times 10 to the 3rd power per microliter)?

0-0.5 times x 10³ per microliter

What is the adult reference range for Eosinophils (times 10 to the 3rd power per microliter)?

Reduction of neutrophils in the blood

What is neutropenia?

Agranulocytosis

What term describes neutropenia that has serious consequences of making individuals susceptible to bacterial and fungal infections?

Inadequate or ineffective granulopoiesis, or accelerated removal or destruction of neutrophils

What are the two general causes of neutropenia?

Aplastic anemia

In what setting can suppression of hematopoietic stem cells, leading to neutropenia, occur?

Exposure to certain drugs

What can cause the suppression of committed granulocytic precursors?

Megaloblastic anemia or myelodysplastic syndrome

Name two disease states associated with ineffective hematopoiesis that can cause neutropenia.

Immunologically mediated injury to neutrophils

What is a cause of accelerated removal or destruction of neutrophils that can be idiopathic, associated with a well-defined immunologic disorder, or caused by drug exposure?

Splenomegaly

What condition leads to the sequestration and destruction of neutrophils, often causing modest neutropenia associated with anemia and thrombocytopenia?

Overwhelming bacterial, fungal, or Rickettsial infections

What condition causes neutropenia due to increased peripheral utilization?

Drug toxicity

What is the most common cause of agranulocytosis?

Alkylating agents and antimetabolites

What two classes of cancer treatments cause generalized suppression of hematopoiesis leading to agranulocytosis?

Antipsychotic agents

Which category of drugs can induce neutropenia by having a toxic effect on granulocytic precursors in the bone marrow?

Sulfonamides

Which drug results in antibody-mediated destruction of neutrophils?

Malaise, chills, and fever

What are early clinical features of neutropenia related to infection?

Below 500 per mm cubed

Serious infections are most likely when the neutrophil count falls below what level?

Infections are often overwhelming and may cause death within hours to days

What are the clinical features of agranulocytosis?

Congenital immunodeficiency diseases, advanced human immunodeficiency virus (HIV) infection, or autoimmune disorders

Name three diseases or therapies where lymphopenia is observed.

Lymphocyte redistribution rather than a decrease in leukocyte count

In settings like autoimmune disorders or acute viral infections, lymphopenia stems from what process?

Type 1 Interferons

What do acute viral infections induce the production of?

Sequestration of activated T cells in lymph nodes

What is one result of Type 1 Interferon activation of T lymphocytes during acute viral infections?

Chronic infection and inflammation (growth factor-dependent)

What is a mechanism and cause of leukocytosis related to increased marrow production?

Hodgkin Lymphoma

Give an example of a paraneoplastic cause of leukocytosis (increased marrow production).

Myeloproliferative neoplasms

What type of neoplasm causes increased marrow production that is growth factor-independent?

Chronic myeloid leukemia

Give an example of a myeloproliferative neoplasm causing leukocytosis via increased marrow production.

Acute inflammation

What is a cause of leukocytosis due to increased release from marrow stores?

Exercise or Catecholamines

Name two causes of leukocytosis due to decreased margination.

Glucocorticoids

What causes leukocytosis due to decreased extravasation into tissues?

Neutrophilic leukocytosis

What type of leukocytosis is associated with acute bacterial infections, especially those caused by pyogenic organisms?

Tissue necrosis, such as myocardial infarction or burns

What is an example of sterile inflammation causing neutrophilic leukocytosis?

Allergic disorders, parasitic infestations, or certain malignancies

Name three causes of eosinophilic leukocytosis.

Pemphigus or dermatitis herpetiformis

Name two autoimmune disorders associated with eosinophilic leukocytosis.

Myeloproliferative neoplasm, such as chronic myeloid leukemia

What does basophilic leukocytosis often indicate?

Chronic infections, bacterial endocarditis, rickettsiosis, or malaria

Name three infections that can cause monocytosis.

Systemic lupus erythematosus

Give an example of an autoimmune disorder that can cause monocytosis.

Ulcerative colitis

Give an example of an inflammatory bowel disease that can cause monocytosis.

Tuberculosis, brucellosis, or viral infections (like hepatitis A, cytomegalovirus, Epstein-Barr virus)

Name three disorders associated with lymphocytosis.

Coarse purple cytoplasmic granules

What are toxic granulations?

Blue cytoplasmic patches of dilated endoplasmic reticulum

What are Döhle bodies?

Origin from hematopoietic progenitor cells

What is the common feature of the heterogeneous group of myeloid neoplasms?

The marrow

Myeloid neoplasms primarily involve which anatomical site?

Spleen, liver, and lymph nodes

Name two secondary hematopoietic organs that can be involved in myeloid neoplasms.

Acute myeloid leukemias

Which category of myeloid neoplasm is characterized by accumulation of immature myeloid forms (blasts) in the bone marrow?

Myelodysplastic syndromes

Which category of myeloid neoplasm is characterized by defective maturation of myeloid progenitors leading to ineffective hematopoiesis and cytopenias?

Myeloproliferative disorders

Which category of myeloid neoplasm is characterized by increased production of one or more types of blood cells?

Acquired oncogenic mutations that impede differentiation

Acute Myeloid Leukemia (AML) is caused by what?

Marrow failure, complications related to anemia, thrombocytopenia, and neutropenia

What are three clinical consequences resulting from the replacement of the marrow with blasts in AML?

After 60 years of age

At what age does the incidence of AML peak?

AML that are associated with particular genetic aberrations

Which WHO category of AML is important because the aberrations correlate with prognosis and guide therapy?

Therapy-related AML

Which WHO category of AML has distinct genetic features and responds poorly to therapy, arising after treatment?

At least 20 percent myeloid blasts in the bone marrow

What percentage of blasts is required for the diagnosis of AML?

Delicate nuclear chromatin, prominent nucleoli, and fine azurophilic granules in the cytoplasm

Describe the morphology of myeloblasts.

CD34 (+)

Which flow cytometry marker, indicative of multipotent stem cells, is expressed in AML?

CD64 (-)

Which flow cytometry marker, indicative of mature myeloid cells, is not expressed in AML?

Neoplastic promyelocytes with abnormally coarse and numerous azurophilic granules

What does a bone marrow aspirate show in Acute Promyelocytic Leukemia?

Auer-rods

What distinctive needle-like azurophilic granules are present in AML with t(15:17)?

t(15:17)

What specific balanced chromosomal translocation is associated with Acute Promyelocytic Leukemia?

Folded or lobulated nuclei

What characterizes the monoblast seen in AML with monocytic differentiation?

50-70 percent

What percentage of AML cases have karyotypic aberrations detected using standard techniques?

t(8;21), inv(16), and t(15;17)

Name the three balanced chromosomal translocations associated with AMLs arising de novo in younger adults.

Deletions or monosomies involving chromosome 5 and 7

What chromosomal abnormalities are typically seen in AMLs following MDS or exposure to DNA-damaging agents?

Translocations involving the MLL gene on chromosome 11q23

What chromosomal abnormality is associated with AML occurring after treatment with topoisomerase II inhibitors?

Fatigue, fever, and spontaneous mucosal and cutaneous bleeding

What are the three most notable complaints in AML patients?

Thrombocytopenia

What causes the abnormal bleeding often prominent in AML patients?

Fungi, Pseudomonas, or Commensals

Name two opportunist organisms that frequently cause infections in AML patients.

AMLs with t(8;21) or inv(16)

Which AML molecular subtypes have a relatively good prognosis with conventional chemotherapy (especially without c-KIT mutations)?

Dismal prognosis

What is the general prognosis for AMLs that follow MDS or genotoxic therapy, or occur in the elderly?

Maturation defects associated with ineffective hematopoiesis

What characterizes Myelodysplastic Syndrome (MDS)?

High risk

What is the risk of MDS transformation to AML?

Secondary to previous genotoxic or radiation therapy (t-MDS)

What is the cause of secondary MDS?

2-8 years

What is the latency period for t-MDS after genotoxic exposure?

Monosomies 5 and 7, Deletions of 5q (5q deletion), 7q (7q deletion), and 20q (20q deletion), or Trisomy 8

Name three clonal chromosomal abnormalities associated with both primary and t-MDS.

Hypocellular

What is the appearance of the bone marrow in a MDS patient associated with isolated monosomy 7 cytogenetic abnormality?

Nucleated red cell progenitors with multilobulated or multiple nuclei

What findings can be seen in the peripheral blood smear of MDS?

Ringed sideroblasts and erythroid progenitors with iron-laden mitochondria

What findings are visible with Prussian blue stain in MDS?

Pseudo-Pelger-Hüet cells

What are the neutrophils with only 2 nuclear lobes instead of the normal 3-4 called, which are observed in MDS?

Elderly (mean age of onset: 70 years old)

Primary MDS is predominantly a disease of what age group?

Weakness, infections, and hemorrhages

What are three symptoms of symptomatic primary MDS cases, due to pancytopenia?

6 months to 5 years

What is the median survival for primary MDS?

4 to 8 months

What is the median survival for therapy-related MDS (t-MDS)?

Within 2 to 3 months of diagnosis

How rapidly does progression to AML occur in t-MDS?

Mutated, constitutively activated tyrosine kinases

What is the common pathogenic feature of myeloproliferative disorders?

They do not impair differentiation

How do the tyrosine kinase mutations underlying MPNs affect differentiation?

Increased proliferative drive in the bone marrow

What is a common clinical and morphologic feature of MPNs?

Extramedullary hematopoiesis

What condition results from the homing of neoplastic stem cells to secondary hematopoietic organs in MPNs?

Spent phase

What variable transformation stage of MPNs is characterized by marrow fibrosis and peripheral blood cytopenias?

Chimeric BCR-ABL gene

What distinguishes Chronic Myeloid Leukemia (CML) from other myeloproliferative disorders?

Reciprocal (9;22)(q35:q11) translocation

What specific chromosomal event creates the BCR-ABL gene in CML?

Philadelphia chromosome

What is the reciprocal (9;22) translocation also known as?

Numerous mature neutrophils and immature forms of granulocytes (metamyelocytes and myelocytes)

What key cells are seen in a CML peripheral blood smear?

Fifth to sixth decades of life

When is the peak incidence for CML?