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Hematology

Lymphoid

Overview of Benign Lymphoid Disorders

  • Definition: Non-cancerous conditions affecting the lymphoid lineage of leukocytes (lymphocytes: T cells, B cells, and NK cells). These disorders involve changes in lymphocyte numbers, appearance, or function that are not due to malignancy
  • Key Features:
    • Usually reactive (secondary) to an underlying condition (e.g., infection, inflammation)
    • Often transient, resolving when the underlying cause is addressed
    • Generally do not involve clonal proliferation or significant dysplasia
  • Benign vs. Malignant: It’s important to differentiate benign lymphoid disorders from malignant lymphomas and leukemias, which are characterized by uncontrolled proliferation of clonal lymphoid cells

Quantitative Changes in Benign Lymphoid Disorders

Quantitative changes refer to alterations in the number of lymphocytes in the peripheral blood

  • Lymphocytosis: Increased number of lymphocytes in the blood (Absolute Lymphocyte Count > 4.0 x 10^9/L in adults)

    • Causes:
      • Viral Infections:
        • Infectious mononucleosis (Epstein-Barr virus - EBV)
        • Cytomegalovirus (CMV) infection
        • Pertussis (Whooping Cough)
        • Other viral infections (e.g., influenza, measles, mumps, rubella)
      • Bacterial Infections:
        • Less common than viral infections
        • Pertussis (Whooping Cough): Characterized by a marked lymphocytosis (often > 20 x 10^9/L) with small, mature lymphocytes
      • Chronic Infections:
        • Tuberculosis (TB)
        • Brucellosis
      • Autoimmune Disorders:
        • Systemic lupus erythematosus (SLE)
        • Rheumatoid arthritis (RA)
      • Drug Reactions:
        • Certain medications (e.g., phenytoin) can cause lymphocytosis
      • Post-Splenectomy:
        • Slight increase in lymphocyte count after spleen removal
      • Lymphoproliferative Disorders:
        • *Must be ruled out, but are not considered “benign.” CLL often has very high lymphocyte counts, smudge cells, and can involve other cell lines over time
    • Laboratory Findings:
      • Elevated WBC count
      • Increased absolute lymphocyte count
      • Peripheral Blood Smear:
        • Small, mature lymphocytes (in some cases)
        • Atypical lymphocytes (reactive lymphocytes) in viral infections (see “Qualitative Changes” below)

  • Lymphopenia: Decreased number of lymphocytes in the blood (Absolute Lymphocyte Count < 1.0 x 10^9/L in adults)

    • Causes:
      • Infections:
        • HIV/AIDS: Destruction of CD4+ T helper cells
        • Severe acute infections (e.g., sepsis)
      • Immunodeficiency Disorders:
        • Severe Combined Immunodeficiency (SCID): Inherited disorders affecting T and B cell development
        • DiGeorge Syndrome: Thymic hypoplasia, leading to T cell deficiency
      • Medications:
        • Corticosteroids: Induce lymphocyte apoptosis
        • Chemotherapy: Damage lymphocytes and other blood cells
        • Immunosuppressants: Cyclosporine, tacrolimus
      • Autoimmune Disorders:
        • Systemic lupus erythematosus (SLE)
        • Rheumatoid arthritis (RA)
      • Radiation Exposure:
        • Damages lymphocytes and bone marrow
      • Malnutrition:
        • Protein-energy malnutrition
        • Zinc deficiency
      • Hodgkin Lymphoma:
        • Advanced stages of the disease can cause lymphopenia
    • Laboratory Findings:
      • Decreased WBC count
      • Decreased absolute lymphocyte count
      • Peripheral Blood Smear: May show normal lymphocytes or abnormal morphology (depending on the underlying cause)
      • HIV Testing: To rule out HIV infection
      • Immunoglobulin Levels: To evaluate for humoral immunodeficiency
      • Flow Cytometry: To enumerate CD4+ T cells (in HIV infection) and assess lymphocyte subsets
      • Lymph Node Biopsy: May be necessary to evaluate for lymphoma or other lymphoproliferative disorders

Qualitative Changes in Benign Lymphoid Disorders

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

  • Reactive Lymphocytes (Atypical Lymphocytes):

    • Description: Lymphocytes with abnormal morphology, typically seen in response to viral infections (especially infectious mononucleosis)
    • Characteristics:
      • Increased cell size
      • Abundant cytoplasm (may be basophilic or vacuolated)
      • Irregular nuclear shape
      • Loosely packed chromatin
      • Prominent nucleoli
    • Significance: Indicate lymphocyte activation in response to an antigen
    • Associated Conditions:
      • Infectious Mononucleosis (EBV)
      • Cytomegalovirus (CMV) infection
      • Toxoplasmosis
      • Viral hepatitis
      • Drug reactions
    • Differentiation from Malignant Lymphocytes:
      • Reactive lymphocytes are typically a mixed population of T and B cells
      • They are not clonal (do not have identical immunoglobulin or T cell receptor gene rearrangements)
      • They lack the specific markers and immunophenotype associated with lymphoma or leukemia

  • Smudge Cells:

    • Description: Damaged lymphocytes that appear as smudged or smeared nuclear chromatin on the peripheral blood smear
    • Significance: Often an artifact caused by mechanical damage during smear preparation
    • Associated Conditions: Can be seen in any condition with increased numbers of fragile lymphocytes, but classically associated with Chronic Lymphocytic Leukemia (CLL). The key point here is to rule out CLL
    • Smudge cells themselves are not diagnostic of any specific benign lymphoid disorder, but their presence should prompt further investigation

  • Lymphocytosis with Atypical Lymphocytes in Infectious Mononucleosis (EBV):

    • Infectious Mononucleosis (Mono): A viral infection caused by the Epstein-Barr virus (EBV)
    • Clinical Features:
      • Fever
      • Sore throat (pharyngitis)
      • Fatigue
      • Lymphadenopathy (swollen lymph nodes, especially in the neck)
      • Splenomegaly (enlarged spleen)
    • Laboratory Findings:
      • Elevated WBC count with lymphocytosis
      • Atypical lymphocytes on peripheral blood smear (often >20% of WBCs)
      • Positive Monospot test (heterophile antibody test)
      • Positive EBV-specific antibodies (e.g., anti-VCA IgM, anti-VCA IgG, anti-EBNA)

  • Lymphocytosis with Atypical Lymphocytes in Cytomegalovirus (CMV) Infection:

    • Cytomegalovirus (CMV) Infection: A common viral infection that can cause a mononucleosis-like illness
    • Clinical Features:
      • Often asymptomatic in healthy individuals
      • Can cause fever, fatigue, malaise, and lymphadenopathy
      • More severe in immunocompromised individuals (e.g., transplant recipients, HIV patients)
    • Laboratory Findings:
      • Elevated WBC count with lymphocytosis
      • Atypical lymphocytes on peripheral blood smear
      • Negative Monospot test
      • Positive CMV-specific antibodies (e.g., CMV IgM, CMV IgG)
      • CMV DNA detection by PCR

  • Other Qualitative Changes:

    • Increased Cytoplasmic Basophilia: May be seen in activated lymphocytes
    • Increased Granularity: May be seen in NK cells
    • Nuclear Abnormalities: Rare in benign conditions but can be seen in some drug reactions

Laboratory Evaluation of Benign Lymphoid Disorders

  • Complete Blood Count (CBC) with Differential:
    • To assess the number and types of lymphocytes in the blood
  • Peripheral Blood Smear Examination:
    • To evaluate the morphology of lymphocytes and identify any qualitative abnormalities
  • Heterophile Antibody Test (Monospot Test):
    • To diagnose infectious mononucleosis (EBV)
  • Epstein-Barr Virus (EBV) Serology:
    • To detect EBV-specific antibodies (e.g., anti-VCA IgM, anti-VCA IgG, anti-EBNA)
  • Cytomegalovirus (CMV) Serology:
    • To detect CMV-specific antibodies (e.g., CMV IgM, CMV IgG)
  • Flow Cytometry Immunophenotyping:
    • To identify lymphocyte subsets (CD4+ T cells, CD8+ T cells, B cells, NK cells)
    • To detect clonal lymphocyte populations (if lymphoma or leukemia is suspected)
  • Lymph Node Biopsy:
    • May be necessary to evaluate for lymphoma or other lymphoproliferative disorders, especially if lymphadenopathy is persistent or unexplained

Key Terms

  • Lymphocyte: A type of white blood cell that includes T cells, B cells, and NK cells
  • Lymphocytosis: An increased number of lymphocytes in the blood
  • Lymphopenia: A decreased number of lymphocytes in the blood
  • Reactive Lymphocyte (Atypical Lymphocyte): An activated lymphocyte with abnormal morphology, typically seen in viral infections
  • Smudge Cell: A damaged lymphocyte that appears as smeared nuclear chromatin
  • Infectious Mononucleosis (Mono): A viral infection caused by the Epstein-Barr virus (EBV)
  • Cytomegalovirus (CMV): A common viral infection that can cause a mononucleosis-like illness
  • Heterophile Antibody Test (Monospot Test): A rapid test for infectious mononucleosis
  • Flow Cytometry Immunophenotyping: A technique to identify cell surface markers and classify leukocytes
  • EBV Serology: Tests to detect EBV-specific antibodies