White Blood Cell Disorders

Objective

• The discussed objectives include non-neoplastic WBC disorders, neoplastic WBC disorders, and acute leukemia

White Blood Cells

• Bone marrow produces key blood cells like myeloid and lymphoid progenitor cells, which differentiate into various blood components
• These components include megakaryocytes, erythrocytes, basophils, neutrophils, eosinophils, T cells, B cells, NK cells, platelets, dendritic cells, macrophages, and plasma cells

WBC Disorder

• WBC disorders are classified as either neoplastic or non-neoplastic
• Neoplastic disorders involve lymphoid or myeloid cells
• Lymphoid cell disorders include ALL, CLL, hairy cell leukemia, prolymphocytic leukemia, multiple myeloma, MGUS, localized plasmacytoma and plasma cell leukemia
• Myeloid cell disorders include CML, AML, polycythemia vera, essential thrombocythemia, and primary myelofibrosis
• Non-neoplastic disorders include leukopenia and leukocytosis

Types of White Blood Cells

• Granulocytes, a type of WBC, include neutrophils, eosinophils, and basophils
• Neutrophils help with phagocytosis
• Eosinophils fight against parasitic infections
• Basophils produce inflammatory and allergic reactions
• Agranulocytes, another type of WBC, include lymphocytes and monocytes
• Lymphocytes produce specific immune responses
• Monocytes fight off bacteria, viruses, and fungi
• Lymphocytes include B lymphocytes, T lymphocytes, and natural killer cells

Peripheral Blood Smear

• A peripheral blood smear can show normal blood leukocyte morphology features, such as eosinophils, basophils, lymphocytes, monocytes, and plasma cells

Bone Marrow Aspirate

• A bone marrow aspirate reveals the normal maturation sequence of granulocytic cells, noting the nucleus gets smaller

White Blood Cell Development

• Myeloblasts have large round nuclei, fine chromatin, one or more nucleoli, and blue cytoplasm with no granules
• Promyelocytes have azurophilic granules in the cytoplasm and over the nucleus
• Myelocytes have round to ovoid nuclei, coarser chromatin, few azurophilic granules and small pink specific granules in the cytoplasm, and nucleoli not seen
• Metamyelocytes (Band) show an indented nucleus, coarse chromatin, and only specific granules
• Neutrophils (Granulocytes) have a segmented nucleus, clumped chromatin, and pink cytoplasm

Non-Neoplastic WBC Disorders

• Centrifugation of whole blood separates it into plasma (55%), buffy coat (leukocytes and platelets, <1%), and erythrocytes (45%)

WBC Terminology

• Leukocytosis refers to an increase in the total white blood cell (WBC) count above the normal upper limit
• Leukopenia refers to a decrease in the total WBC count below the normal lower limit

Leukocytosis Subtypes

• Neutrophilia: Neutrophil count is greater than 7.0 × 10^9/L
• Eosinophilia: Eosinophil count is greater than 0.5 × 10^9/L
• Basophilia: Basophil count is greater than 0.1 × 10^9/L
• Lymphocytosis: Lymphocyte count is greater than 3.5 × 10^9/L
• Monocytosis: Monocyte count is greater than 1.0 × 10^9/L

Leukopenia Subtypes

• Neutropenia: Neutrophil count less than 2 × 10^9/L
• Lymphopenia: Lymphocyte count less than 1.5 × 10^9/L

Non-Neoplastic WBC Disorder - Leukocytosis

• Neutrophilia associates with acute bacterial infections, myocardial infarction, burns, uremia, neoplasms, hemorrhage or hemolysis, and myeloid growth factor treatments (G-CSF, GM-CSF)
• Eosinophilia associates with allergic disorders, drug sensitivity, parasitic infestations, collagen vascular disorders, malignancies, myeloproliferative neoplasms, and GM-CSF treatments
• Basophilia associates with neoplastic conditions like CML and reactive conditions like ulcerative colitis, myxoedema, and smallpox or chickenpox infections
• Monocytosis associates with chronic bacterial infections, malaria, Hodgkin disease, AML, collagen vascular diseases, certain chronic myeloproliferative neoplasms, and IBD
• Lymphocytosis associates with acute (CMV) and chronic (TB) infections, neoplastic conditions like CLL, ALL, NHL, and thyrotoxicosis

Non-Neoplastic WBC Disorder - Leukopenia

• Neutropenia results from inadequate or ineffective granulopoiesis, accelerated neutrophil removal, infections/hypersplenism, or altered distribution
• Lymphopenia can be congenital or acquired, such as due to HIV, miliary TB, treatments with corticosteroids, or advanced Hodgkin disease

Neutrophilia

• Acute bacterial infections with pyogenic bacteria create abscesses
• Myeloid growth factors (G-CSF, GM-CSF) like Filgrastim (Neupogen) and Lenograstim (Granocyte) treat cancer patients that have neutropenia
• Myeloid growth factors can also potentially cause neutrophilia

Eosinophilia

• Conditions linked to eosinophilia include:
  • Allergic disorders
  • Drug sensitivity
  • Parasitic infestations (e.g., hydatid cyst)
  • Collagen vascular disorders (e.g., SLE, Rheumatoid Arthritis, vasculitis)
  • Certain malignancies (e.g., ALL, Lymphoma)
  • Myeloproliferative neoplasms
  • Treatment with GM-CSF

Basophilia

• Neoplastic basophilia often presents in chronic myeloid leukemia
• Reactive basophilia can occur in ulcerative colitis, myxoedema, or smallpox/chickenpox infections

Monocytosis

• Monocytosis relates to chronic bacterial infections such as tuberculosis or bacterial endocarditis and syphilis
• Monocytosis can also relate to malaria, collagen vascular diseases, Hodgkin disease/AML, certain myeloproliferative neoplasms, and inflammatory bowel diseases

Lymphocytosis

• Lymphocytosis is categorized by infections, neoplastic conditions, and thyrotoxicosis
• Acute Infections: Infectious mononucleosis (EBV), rubella, mumps, infectious hepatitis, CMV, HIV, herpes, B. pertussis
• Chronic Infections: typhoid fever, syphilis, healing TB, toxoplasmosis
• Neoplastic includes chronic/acute lymphoid leukemias and non-Hodgkin lymphoma

Neutropenia

• Defined as a reduction below normal of the number of neutrophils in peripheral blood
• Inadequate or ineffective granulopoiesis stems from generalized marrow failure or isolated neutropenia
• Congenital or acquired factors precipitate accelerated removal or destruction of neutrophils
• Altered distribution stems from stress and certain drugs

Lymphopenia

• A reduction below the normal lymphocyte count in peripheral blood
• Lymphopenia is associated with congenital immunodeficiency diseases
• Lymphopenia also associated with advanced HIV, miliary TB, corticosteroid treatments and advanced Hodgkin disease

Acute Leukemia - Clinical Presentation

• A 40-year-old man presents with weakness and sore throat for one week
• The patient also has pale color, petechial rash on his legs, inflamed throat, cervical and axillary lymph node enlargement, and splenomegaly
• Laboratory Investigations includes a complete blood count (CBC) with differential diagnosis

Acute Leukemia

• Acute leukemia is an aggressive clonal malignant transformation of hematopoietic stem or early progenitor cells (blasts) leading to uncontrolled proliferation of blast cells in the bone marrow

Acute Leukemia Details

• The proliferation leads to a spillover of blast cells into the peripheral blood and infiltration of other organs
• Subtypes include acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML)
• The age range of people affected is variable

Clinical Features

• Acute leukemia is classified into childhood acute leukemia and adult acute leukemia
• Childhood acute leukemia is lymphoblastic (ALL)
• Adult acute leukemia is myeloblastic (AML)

AL Symptoms

• Symptoms stem both from bone marrow failure and infiltration of organs/tissues by leukemic cells
• Bone marrow failure causes anemia, neutropenia, and thrombocytopenia

AL Symptoms Resulting from Bone Marrow Failure

• Anemia: pallor, weakness, fatigue, lethargy, dyspnea on exertion, angina, and palpitation
• Neutropenia: fever and infections from reduced immunity, especially skin and respiratory infections
• Thrombocytopenia: bleeding manifestations, like petechiae and ecchymosis

AL - Organ and Tissue Infiltration

• Organ and tissue infiltration of leukemic cells causes splenomegaly, hepatomegaly, bone pain, and arthralgia

Diagnosing AL

• More that 20%
• BMA is necessary to confirm the diagnosis

Blood Film Findings indicative of AL

• Anemia
• WBC levels can be normal, high, or low (Neutropenia is common)
• Decreased Platelets

Classifying Acute Leukemia

• Classifications are based on morphology of blasts, cytochemistry, immunophenotyping, and genetic analysis
• There are two major types of AL: Acute Lymphoid Leukemia (ALL) and Acute Myeloid Leukemia (AML)

AL: ALL vs AML - Morphology

• Lymphoblasts have one or two nucleoli, coarse clumped chromatin, and less cytoplasm with no Auer rods
• Myeloblasts have multiple nucleoli, finer chromatin, more cytoplasm, and may contain granules or Auer rods
• The nuclei of lymphoblasts exhibit coarse and clumped chromatin with one or two nucleoli
• Myeloblasts show finer chromatin, multiple nucleoli, and larger cytoplasm, potentially with granules or Auer rods

AL - Cytochemistry

• Myeloperoxidase (MPO) yields a negative result in ALL and a positive result in AML
• Sudan Black B (SBB) yields a negative result in ALL but a positive result in AML, particularly with Auer rods
• Non-specific esterase yields a negative result in ALL but a positive result in M4 and M5 subtypes of AML
• Periodic Acid-Schiff (PAS) staining will be positive in many cases of ALL and positive in M6 subtype of AML (fine blocks)
• Acid Phosphatase is positive in certain cases

AL - Immunophenotyping

• Immunophenotyping (IPT) can be measured using flow cytometry or immunohistochemistry and is useful for AL typing and subtyping
• CD79a serves as a specific marker for B-cells while CD3 marks T-cells
• Anti-myeloperoxidase (MPO) is a specific myeloid marker

AL - Genetic Analysis

• In ALL, hyperploidy (>50 chromosomes/cell) correlates with good prognosis and associates with t(12:21)
• Poor outcomes associates with the presence of the 11q23 and Philadelphia chromosome (Ph+)
• In AML, good outcome correlates with t(8:21) and t(15:17) while conversely, poor outcome correlates with Ph+ and t(6:9)
• Philadelphia chromosome relates to a bad prognosis in both AML and ALL

Summary

• Reactive leukocytosis is more frequently encountered than neoplastic states
• Absolute leukocytes counts are more important than percentages
• The cutoff point is 20% when determining the diagnosis of AL
• Morphology, Cytochemistry, IPT and Genetic Analysis is required to reach a diagnosis and classify AL