Myeloid

Overview of Benign Myeloid Disorders

Definition: Non-cancerous conditions affecting the myeloid lineage of leukocytes (neutrophils, eosinophils, basophils, and monocytes).
Key Features:
- Usually reactive (secondary) to an underlying condition, rather than being primary disorders of the bone marrow.
- Often transient, resolving when the underlying cause is addressed.
- Generally, do not involve clonal proliferation or significant dysplasia (abnormal cell development).

Quantitative Changes in Benign Myeloid Disorders

Quantitative changes refer to alterations in the number of specific types of myeloid cells in the peripheral blood.

Neutrophilia: Increased number of neutrophils in the blood (Absolute Neutrophil Count > 7.7 x 10^9/L in adults)
- Causes:
  - Infections: Bacterial infections are the most common cause of neutrophilia
  - Inflammation: Tissue injury, surgery, burns, autoimmune diseases
  - Stress: Emotional stress, exercise
  - Medications: Corticosteroids, lithium
  - Myeloproliferative Neoplasms (MPNs): Must be ruled out, but are not considered “benign”
  - Physiologic: Newborns and pregnant patients will have slightly higher ranges
- Mechanisms:
  - Increased release of neutrophils from the bone marrow storage pool
  - Increased production of neutrophils in the bone marrow (stimulated by G-CSF and other cytokines)
  - Decreased migration of neutrophils into tissues
- Leukemoid Reaction: An extreme neutrophilic response (WBC count > 50 x 10^9/L) that mimics leukemia.
  - Key Features:
    - Absence of blasts in the peripheral blood
    - Elevated leukocyte alkaline phosphatase (LAP) score (see below)
    - Lack of clonal cytogenetic abnormalities
- Laboratory Findings:
  - Elevated WBC count
  - Increased absolute neutrophil count
  - May see a “left shift” with increased band neutrophils and, occasionally, metamyelocytes and myelocytes on the peripheral smear
  - Toxic granulation, Dohle bodies, and vacuolization may be present in neutrophils (see “Qualitative Changes” below)
Neutropenia: Decreased number of neutrophils in the blood (Absolute Neutrophil Count < 2.0 x 10^9/L in adults)
- Causes:
  - Drug-Induced: Chemotherapy, antibiotics (e.g., trimethoprim-sulfamethoxazole), anticonvulsants
  - Infections: Viral infections (e.g., influenza, HIV), severe bacterial infections (sepsis)
  - Autoimmune Disorders: Systemic lupus erythematosus (SLE), rheumatoid arthritis
  - Nutritional Deficiencies: Vitamin B12 or folate deficiency
  - Bone Marrow Disorders: Aplastic anemia, myelodysplastic syndromes (MDS)
  - Ethnic Neutropenia: Benign condition seen in individuals of African descent
- Mechanisms:
  - Decreased production of neutrophils in the bone marrow
  - Increased destruction of neutrophils in the peripheral blood
  - Sequestration of neutrophils in the spleen
- Clinical Significance: Increased risk of bacterial and fungal infections.
- Laboratory Findings:
  - Decreased WBC count
  - Decreased absolute neutrophil count
  - Peripheral blood smear: May show normal neutrophils or abnormal morphology (e.g., dysplastic neutrophils in MDS)
  - Bone marrow examination: May be necessary to evaluate for bone marrow disorders
Monocytosis: Increased number of monocytes in the blood (Absolute Monocyte Count > 1.0 x 10^9/L in adults)
- Causes:
  - Chronic Infections: Tuberculosis, fungal infections, bacterial endocarditis
  - Inflammatory Conditions: Inflammatory bowel disease (IBD), sarcoidosis
  - Malignancies: Hodgkin lymphoma, non-Hodgkin lymphoma, myelodysplastic syndromes (MDS)
  - Recovery from Neutropenia
- Clinical Significance: Often associated with chronic inflammatory or infectious processes.
- Laboratory Findings:
  - Elevated WBC count
  - Increased absolute monocyte count
  - Peripheral blood smear: May show normal or activated monocytes
Monocytopenia: Decreased number of monocytes in the blood (Absolute Monocyte Count < 0.2 x 10^9/L in adults)
- Causes:
  - Aplastic Anemia: Bone marrow failure leads to decreased production of all blood cell lines
  - Hairy Cell Leukemia: Malignant B cells infiltrate the bone marrow, suppressing normal hematopoiesis
  - Glucocorticoid Therapy: Corticosteroids can cause monocytopenia
- Clinical Significance: May increase susceptibility to certain infections.
- Laboratory Findings:
  - Decreased WBC count
  - Decreased absolute monocyte count
  - Peripheral blood smear: May show normal or abnormal cells, depending on the underlying cause
  - Bone marrow examination: Often necessary to evaluate for bone marrow disorders
Eosinophilia: Increased number of eosinophils in the blood (Absolute Eosinophil Count > 0.4 x 10^9/L in adults)
- Causes:
  - Parasitic Infections: Especially helminth infections (e.g., hookworm, roundworm)
  - Allergic Reactions: Asthma, allergic rhinitis, eczema
  - Drug Reactions
  - Certain Malignancies: Hodgkin lymphoma, T-cell lymphoma
  - Addison’s Disease: Adrenal insufficiency
  - Hypereosinophilic Syndrome (HES): A rare disorder characterized by persistent eosinophilia and organ damage
- Clinical Significance: Can indicate parasitic infection, allergic disease, or other underlying conditions
- Laboratory Findings:
  - Elevated WBC count
  - Increased absolute eosinophil count
  - Peripheral blood smear: May show normal or activated eosinophils
Basophilia: Increased number of basophils in the blood (Absolute Basophil Count > 0.1 x 10^9/L in adults)
- Causes:
  - Myeloproliferative Neoplasms (MPNs): Chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET)
  - Allergic Reactions: Urticaria, angioedema
  - Hypothyroidism
  - Infections: Certain viral infections
- Clinical Significance: Often associated with MPNs or allergic reactions.
- Laboratory Findings:
  - Elevated WBC count
  - Increased absolute basophil count
  - Peripheral blood smear: May show normal or increased basophils

Qualitative Changes in Benign Myeloid Disorders

Qualitative changes refer to alterations in the appearance or function of myeloid cells. These changes are often observed on the peripheral blood smear.

Toxic Granulation:
- Description: Prominent, dark-blue or purple granules in the cytoplasm of neutrophils
- Significance: Indicates accelerated granulopoiesis in response to severe infection or inflammation
- Mechanism: Abnormal maturation of neutrophils in the bone marrow, leading to increased granule formation
- Other Associated Findings: Dohle bodies, cytoplasmic vacuolization
Döhle Bodies:
- Description: Light-blue or gray-blue, irregular inclusions in the cytoplasm of neutrophils
- Significance: Represent aggregates of rough endoplasmic reticulum (RNA)
- Associated Conditions: Bacterial infections, burns, trauma, pregnancy
Cytoplasmic Vacuolization:
- Description: Presence of vacuoles (clear, round spaces) in the cytoplasm of neutrophils, monocytes, or lymphocytes
- Significance: Can indicate phagocytosis of bacteria or fungi, toxic effects of drugs, or artifacts due to improper staining
- Associated Conditions: Infections, alcohol toxicity, exposure to certain chemicals
Pelger-Huët Anomaly:
- Description: Neutrophils with bilobed or unlobed nuclei (” pince-nez” appearance)
- Inherited (True) Pelger-Huët Anomaly: Benign condition with normal neutrophil function.
  - Caused by a mutation in the Lamin B Receptor gene (LBR)
  - All neutrophils are affected
- Acquired (Pseudo) Pelger-Huët Anomaly: Occurs in myelodysplastic syndromes (MDS) and other conditions affecting neutrophil maturation.
  - Only some neutrophils are affected
  - May be associated with other dysplastic features (e.g., abnormal granulation)
- Clinical Significance: Important to distinguish true Pelger-Huët anomaly from pseudo-Pelger-Huët anomaly, as the latter may indicate a more serious underlying disorder.
Alder-Reilly Anomaly:
- Description: Large, azurophilic (purple-red) granules in all types of leukocytes (neutrophils, lymphocytes, monocytes)
- Significance: Results from abnormal lysosomal storage due to a deficiency in certain mucopolysaccharidases
- Associated Conditions: Mucopolysaccharidoses (MPS), a group of inherited metabolic disorders
- Distinction from Toxic Granulation: Alder-Reilly granules are larger and more prominent, and are present in all types of leukocytes, while toxic granulation is usually limited to neutrophils
May-Hegglin Anomaly:
- Description: Large, pale-blue inclusions (Döhle bodies) in neutrophils, eosinophils, basophils, and monocytes, accompanied by thrombocytopenia and giant platelets
- Significance: Caused by a mutation in the MYH9 gene, which encodes nonmuscle myosin heavy chain IIA
- Clinical Features: Mild to moderate thrombocytopenia with bleeding tendencies (e.g., easy bruising, epistaxis)
- Laboratory Findings:
  - Thrombocytopenia
  - Giant platelets on peripheral blood smear
  - Döhle-like inclusions in leukocytes
Chédiak-Higashi Syndrome:
- Description: Rare autosomal recessive disorder characterized by giant granules in neutrophils, eosinophils, basophils, monocytes, and lymphocytes
- Significance: Caused by a mutation in the LYST gene, which regulates lysosomal trafficking
- Clinical Features:
  - Partial albinism (skin and hair)
  - Recurrent bacterial infections
  - Neurological abnormalities
  - Increased susceptibility to lymphoma
- Laboratory Findings:
  - Giant granules in leukocytes on peripheral blood smear
  - Neutropenia
  - Thrombocytopenia
  - Impaired neutrophil chemotaxis and killing

Key Laboratory Tests for Benign Myeloid Disorders

Complete Blood Count (CBC) with Differential:
- To assess the number and types of leukocytes in the blood
Peripheral Blood Smear Examination:
- To evaluate the morphology of leukocytes and identify any qualitative abnormalities
Special Stains:
- May be used to identify specific types of granules or inclusions in leukocytes
Flow Cytometry:
- To identify cell surface markers and classify leukocytes
Bone Marrow Aspiration and Biopsy:
- May be necessary to evaluate for bone marrow disorders or malignancies
Genetic Testing:
- To identify mutations associated with certain inherited leukocyte disorders (e.g., Pelger-Huët anomaly, Chédiak-Higashi syndrome)

Key Terms

Leukocyte: A white blood cell; a general term for cells involved in the immune system
Myeloid Cells: Leukocytes that develop from a myeloid progenitor cell in the bone marrow; includes neutrophils, eosinophils, basophils, and monocytes
Granulocytes: A type of leukocyte characterized by granules in their cytoplasm; includes neutrophils, eosinophils, and basophils
Neutrophil: The most abundant type of WBC; primarily responsible for fighting bacterial and fungal infections
Eosinophil: A type of WBC primarily involved in defense against parasites and allergic reactions
Basophil: A type of WBC involved in allergic reactions and inflammation; contains histamine and heparin in its granules
Monocyte: A type of WBC that circulates in the blood and then differentiates into a macrophage or dendritic cell in tissues
Macrophage: A tissue-resident phagocyte that engulfs and destroys pathogens, debris, and dead cells; also involved in antigen presentation and cytokine production
Leukopoiesis: The production of white blood cells
Neutrophilia: An increased number of neutrophils in the blood
Neutropenia: A decreased number of neutrophils in the blood
Monocytosis: An increased number of monocytes in the blood
Monocytopenia: A decreased number of monocytes in the blood
Eosinophilia: An increased number of eosinophils in the blood
Basophilia: An increased number of basophils in the blood
Leukemoid Reaction: A benign increase in white blood cells (usually neutrophils) that mimics leukemia
Absolute Neutrophil Count (ANC): The actual number of neutrophils in a sample of blood; used to assess the risk of infection in patients with neutropenia
Left Shift: The presence of increased numbers of immature neutrophils (e.g., bands, metamyelocytes, myelocytes) in the peripheral blood, indicating increased bone marrow activity
Qualitative Changes: Alterations in the appearance or function of cells
Toxic Granulation: Prominent, dark granules in neutrophils, indicating severe infection or inflammation
Döhle Bodies: Light-blue cytoplasmic inclusions in neutrophils, consisting of rough endoplasmic reticulum; seen in infection, burns, and other conditions
Cytoplasmic Vacuolization: The presence of vacuoles (clear spaces) in the cytoplasm of cells, often indicating phagocytosis or toxic effects
Pelger-Huët Anomaly: Neutrophils with bilobed or unlobed nuclei
Alder-Reilly Anomaly: Large, azurophilic granules in all types of leukocytes, seen in mucopolysaccharidoses
May-Hegglin Anomaly: Large, pale-blue inclusions (Döhle bodies) in leukocytes, accompanied by thrombocytopenia and giant platelets
Chédiak-Higashi Syndrome: A rare autosomal recessive disorder characterized by giant granules in leukocytes and other cells
Dysplasia: Abnormal cell development or maturation
Bone Marrow Aspiration and Biopsy: Procedures to collect and examine bone marrow cells

Benign Disorders

Lymphoid