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WBC Disorders (Diagnostic Stuff (PE Findings Lab Values Smears (:arrow_up:…

- - - - Basophilia
        
        CML
      - Lymphocytosis
    - - Rash
        
        Adult T-Cell Leukemia
        
        Mycosis Fungoides
      - Rash, Plaques and Nodules
        
        Mycosis Fungoides
- - - - Neoplastic Proliferation of Mature Myeloid Cells
        
        :arrow_up: Granulocytes
        
        t(9;22)
        
        :arrow_up:Basophils
        
        :arrow_up:Granulocytes
        
        LAP (Negative)
        
        Chronic Myeloid Leukemia
        Uncontrolled mature granulocyte production, mostly neutrophils but also basophils and eosinophils.
        Caused by:
        
        9;22 translocation
        
        Forms the BCR-ABL fusion protein with constantly active tyrosine kinase activity
        
        Mutation is in pluripotent stem cell so CML can often progress into AML or ALL
        
        Since cells of the myeloid lineage are in greater numbers that lymphoid lineage we expect more (2/3rds) to transform into AML and the other 1/3rd into ALL
        
        Features:
        
        Myelocyte predominance vs metamyelocyte
        
        Splenomegaly
        
        Basophilia and Eosinophilia
        
        Management
        
        Imatinib
        
        Enlarging Spleen means disease progression
        
        1/3 transforms into ALL
        
        2/3 transforms into AML
        
        :arrow_up:Granulocytes Only
        
        LAP (Positive)
        
        Leukemoid Reaction (Non-neoplastic)
        
        CML vs Leukemoid Reaction and need to be distinguished since both will show hypercellularity
        
        CML
        
        Negative Leukocyte Alkaline Phosphatase (LAP) stain
        
        :arrow_up::arrow_up: Basophils
        
        t(9;22) chromosomal abnormality
        
        Leukemoid Reaction (due to an infection)
        
        Positive Leukocyte Alkaline Phosphatase (LAP) Stain
        
        :left_right_arrow: Basophils
        
        Jak-STAT Mutation
        
        Lots of Itching
        
        :arrow_up:RBCs
        
        Elevated RBC can be due to:
        
        Reactive Polycythemia
        
        Renal Cell Carcinoma
        
        Polycythemia Vera
        
        :arrow_up: EPO
        
        More EPO means more RBCs are produced in the bone marrow
        
        :left_right_arrow: SaO2
        
        Ectopic EPO production causing elevation in RBCs
        
        Oxygen saturation of Hemoglobin is normal
        
        1 more item...
        
        :arrow_down:SaO2
        
        Lung disease and hypoxemia decrease Oxygen Saturation of Hemoglobin
        
        1 more item...
        
        :arrow_down: EPO
        
        :left_right_arrow: SaO2
        
        EPO decreased since circulating blood levels are already too high. However, RBCs grow without EPO stimulation
        
        Oxygen saturation is normal
        
        Polycythemia Vera
        Elevation in RBCs, platelets, and granulocytes
        Features:
        Symptoms are due to hyperviscosity of blood
        
        Blurry vision and headache
        
        Flash face due to congestion of RBCs in face (Plethora)
        
        Itching after bathing
        
        due to increased number of mast cells that release histamine when exposed to heat
        
        Management
        1. Phlebotomy
        
        Hydroxyurea
        
        No Itching
        
        Dry Tap
        
        :arrow_up:Megakaryocytes
        
        Myelofibrosis
        
        Tear Drop Blood Cells
        
        Pancytopenia
        
        Features
        
        Megakaryocytes produce excess Platelet-Derived Growth Factor causing marrow fibrosis
        
        Marrow Fibrosis leads to tear-drop RBCs that are damaged as they are squeezed out of the marrow
        
        Splenomegaly due to extramedullary hematopoiesis, not from splenic invasion
        
        Pancytopenia results from marrow fibrosis leading to risk of infection, thrombosis, and bleeding
        
        No Marrow Fibrosis
        
        :arrow_up:Platelets
        
        Essential Thrombocythemia
        Elevation in Platelets, RBCs, and granulocytes
        Features:
        1. Increased risk of bleeding
        
        No significant risk for Gout
        
        Rarely progresses to marrow fibrosis or Acute Leukemia
  - - - No Immunoglobulin Production
        
        Lymphoma
        
        No Cytokine Secretion
        
        Non-Hodgkins
        60% of cases
        Cells: Malignant Lymphoid Cells
        Mass: Malignant Lymphoid Cells
        Spread: Diffuse; extranodal
        Leukemic Phase: Occurs
        
        Some Lymph Node Architecture Maintained
        
        Due To Chronic Inflammatory Condition
        
        1 more item...
        
        Due to Translocation
        
        All are due to proto-oncogenes being moved to chormosome 14 where Heavy Chain is expressed a bunch causing the translocated gene sequence be expressed more than normal. The translated sequences are cell cycle modulators (Cyclin D1, C-Myc) or mediators of apoptosis (BCL2)
        
        3 more items...
        
        No Normal Architecture
        
        Diffuse Large B-Cell Lymphoma
        
        Neoplastic proliferation of Large B cells
        Most Common Non-Hodgkin's Lymphoma
        
        Very Aggressive
        
        Presents in Late Adulthood
        
        Causes:
        
        Sporadic or transforms from lower grade lymphoma
        
        Follicular Lymphoma or Chronic Lymphocytic Leukemia
        
        Features
        
        Enlarging Lymph node
        
        Enlarging Extranodal Mass
        
        Cytokine Secretion
        
        B- Symptoms
        
        Hodgkins Lymphoma
        40% of cases
        Cells: Reed-Sternberg Cells
        
        Large B cells with multi lobed nuclei and prominent nucleoli
        
        Derived from Germinal Center B-Lymphocytes
        
        Secrete Cytokines --> B Symptoms
        
        Fever, chills, weight loss, and Night sweats
        
        Similar to Tuberculosis
        
        Attracts reactive lymphocytes
        
        Plasma cells, macrophages, and eosinophils
        
        May lead to fibrosis
        
        Owl-Eyed Nuclei
        
        Features:
        
        CD15
        
        CD30
        Mass: Predominantly reactive cells (inflammatory cells and fibrosis, with RSCells at center
        Spread: Contiguous; rarely extranodal
        Leukemic Phase: Does not occur
        
        Reed-Sternberg cells in lacunar spaces
        
        Lots of Eosinophils (IL-5)
        
        Mixed Cellularity
        
        Lots of Eosinophils
        
        RS cells produce IL-5
        
        No Lymphocytes
        
        Lymphocyte-Depleted
        
        Most Aggressive
        
        RS cells are so messed up that they cannot produced functional cytokines
        
        Features:
        
        Usually seen in Eldery or HIV (+)
        
        Lots of Lymphocytes
        
        Lymphocyte-Rich
        
        Best-prognosis
        
        RS cells here are producing an effective cytokine
        
        RS cells with Lacunar Cells
        
        Nodular Sclerosis
        
        Most-Common Subtype
        
        Features:
        
        Enlarging Cervical/Mediastinal lymph node in young adult; usually female
        
        Lymph node is divided by bands of sclerosis
        
        RS cells in lake-like spaces (lacunar cells)
        
        Dendritic Cell Disorders
        
        :arrow_up: Langerhans Histiocytes
        
        Langerhans Cell Histiocytosis
        
        Neoplastic proliferation of Langerhans Cells
        
        Langerhans cells are specialized dendritic cells found predominantly in the skin
        
        Derived from bone marrow monocytes
        
        Present antigens to Naive T-cells
        
        Features
        
        Birbeck (Tennis Racket) granules
        
        (+)S100 & (+)CD1a
        
        No Skin Involvement
        
        Benign
        
        Eosinophilic Granuloma
        
        Benign proliferation of Langerhans cells in the bone
        
        Features:
        
        1. Pathologic fractures in adolescent
        
        Elevated Langerhans cells
        
        Elevated Eosinophils
        
        Skin Involvement
        
        Malignant
        
        Scalp Rash
        
        Hand-Schuller-Christian Disease
        
        Malignant Proliferation of Langerhans Cells
        
        Features:
        
        1. Scalp Rash
        
        2. Lytic Skull defects
        
        3. Diabetes Insipidus
        
        4. Exophthalmos in child
        
        Skin Rash
        
        Letterer-Siewe Disease
        
        Malignant Proliferation of Langerhans Cells
        
        Features:
        
        Skin Rash
        2. Cystic Skeletal defects in an infant
        
        Multiple organs may be involved; rapidly fatal
      - Lots of Immunoglobulins
        
        Plasma Cell Disorders
        
        :arrow_up: IgM
        
        Waldenstrom Macroglobulinemia
        
        B cell lymphoma with monoclonal IgM production
        
        Features
        
        Generalized lymphadenopathy
        
        Increased serum protein with M spike (IgM)
        
        Visual and neurologic deficits
        
        Retinal hemorrhage or stroke
        
        IgM (large pentamer) cases serum hyperviscosity
        
        Management
        
        Plasmapheresis - to remove IgM from the serum
        
        :arrow_up: IgG + IgA
        
        No Lytic Bone Lesions
        
        :arrow_down: Ca2+
        
        Monoclonal Gammopathy of Undetermined Significance
        
        B cell lymphoma with monoclonal IgM production
        
        Common in elderly
        
        1% of those with MGUS develop multiple myeloma each year
        
        Increases serum protein with M Spike on SPEP
        
        No lytic bone lesions
        
        No hypercalcemia
        
        No AL Amyoid
        
        No Bence-Jones proteinuria
        
        Lytic Bone Lesions
        
        :arrow_up: Ca2+
        
        Multiple Myeloma
        
        Most common primary malignancy of bone
        
        Metastatic malignancies are still the most common cause of bone cancer (PB-KTL)
        
        Prostate, Breast, Kidney, Thyroid, Lung
        
        High serum IL-6
        
        Causes plasma cell growth and immunoglobulin production
        
        Features:
        
        1. Bone Pain
        
        Punched out lytic lesions in the vertebrae and skull
        
        Plasma cells activate RANK receptor on osteoclasts causing them to deteriorate bone
        
        :arrow_up: Ca2+
        
        :arrow_up: Alkaline phosphatase
        
        :arrow_up: Fracture Risk
        2. Elevated Serum Protein
        
        Immunoglobulin production in excess
        
        M Spike on Serum Electrophoresis (at gamma position on right. Albumin spike on left)
        3. Increased Risk of infection
        
        Monoclonal antibodies have no diversity and are therefore useless; infection is most common cause of death
        4. Rouleaux Formation
        
        Increased serum proteins decreases the charge between RBCs
        5. Primary AL Amyloidosis
        
        Free light chains circulate in serum and deposit in all tissues
        6. Proteinuria
        
        Free light Chans are excreted in the urine as Bence Jones protein; deposition in kidney tubules leads to risk of renal failure myeloma kidney
    - - Lymphadenopathy
        
        Lymph first passes by Primary Follicles with waiting, non-activated B cells or recirculating memory cells
        
        If in infection is present a Secondary Follicle will be present containing a germinal center with actively replicating B cells, and a Mantle zone with non activated B cells
        
        If chronic inflammation is present you'll see a 3rd layer of cells known as the Marginal Zone
        
        Painful
        1. Draining acute infection
        
        Paracortex Hyperplasia (T-Cell)
        T-cells are actively replicating here so that CD8+ cells can be made
        
        Viral Infection
        
        Infectious Mononucleosis
        
        Sinus Histiocyte Hyperplasia
        Enlarged when Lymph node is draining tissue with cancer
        
        Follicular Hyperplasia (B-Cell)
        B cells are replicated because of an antigen constantly being presented to T-cells which activate B-cells via their B7 receptors
        
        Rheumatoid Arthritis
        
        SLE
        
        Early HIV before CD4+ cells fail
        
        Features:
        
        (+) Normal Kappa to Lambda Light chain Ratio 3:1
        
        (+) Tingible Body Macrophages
        
        Contains Clearings around B cells in Germinal cells indicating that Macrophages are consuming B cells that have failed somatic hypermutation
        
        Compare Follicular to Lymphoma
        
        No Tingible Body Macrophages are present (no clearings where macrophages are killing B cells that fail somatic hypermutations).
        
        - Means that no B cells are failing somatic hypermutations due to BCL2 over expression
        
        Painless
        
        1. Chronic Inflammation
        
        2. Metastatic Carcinoma
        
        3. Lymphoma
        
        With B Symptoms : Hodgkin Lymphoma
        
        No B Symptoms; Late Adulthood : Non-Hodgkin Lymphoma
- - - - TdT Positive
        
        Proliferation of Lymphoid Blasts
        
        Acute Lymphoblastic Leukemia
        
        Most commonly in Children under 5
        
        Down syndrome association
        
        >25% bone marrow lymphoblasts
        
        CD10
        
        CD19
        
        CD20
        
        Kids
        
        t (12;21) B-ALL
        Most Common
        
        Requires Prophylaxis to scrotum and CSF
        
        Can spread to testicles and meninges
        
        Excellent Prognosis
        
        Blasts in the meninges - hence the necessity to use chemotherapy on the CSF
        
        Adults
        
        t (9;22) B-ALL
        
        Bad prognosis
        
        CD2 to CD8
        
        No CD10
        
        Teenagers
        
        T-ALL
        
        Mediastinal (thymus) mass
      - TdT Negative
        
        Proliferation of Myeloid Blasts
        
        Acute Myeloid Leukemia
        
        Older Adults (50-60)
        
        MPO (-)
        
        Auer Rod (-)
        
        Acute Monocytic Leukemia
        
        Monocyte proliferation; usually lack MPO
        
        Blasts infiltrate the gums
        
        Acute Mekakaryoblastic Anemia
        
        Megakaryoblast proliferation; lack MPO
        
        Down syndrome Association before the age of 5
        
        Eosinophilic AML Subtype
        
        Due to A chromosome 16 inversion leading to the M4Eo subtype
        
        MPO (+)
        
        Auer Rod (+)
        
        t(15;17) Acute Promyelocytic Anemia
        
        These cells would likely become neutrophils, hence why they have myeloperoxidase
        
        Translocation of retinoid acid receptor (RAR) on chromosome 17 to chromosome 15 preventing differentiation of mature cells
        
        Promyelocytes have a lot of granules increasing the risk for DIC
        
        RX: with All-Trans-Retinoic Acid (ATRA)
        
        Image shows prominent Auer Rod (red arrow) and a punched out nucleoli on the top of the cell indicating that this is a blast
    - - Myelodysplastic Syndrome
        Exposure to alkylating agents or radiotherapy exposure. Eventually this can lead to AML
        
        Cytopenias
        
        Hypercellular bone marrow
        
        Abnormal maturation of cells
        
        Increased blasts
        
        Patients often die from infection or bleeding, some may progress to AML
  - - - Proliferation of Mature CD4+ T-Cells
        
        Rash, Plaques, and Nodules
        
        Mycosis Fungoides
        
        Clinical Features
        
        Localized skin rash, plaques, and nodules.
        
        These Nodules contain aggregates of neoplastic cells called Pautrier Microabscesses
        
        Spread to Blood
        
        Sezary Syndrome
        
        Lymphocytes with Cerebriform Nuclei (Sezary Cells). Look like little brains
        
        Rash
        
        Adult T-Cell Leukemia
        
        Second Most Common Malignancy of Bone
        
        HTLV-1 association
        
        Seen in Japan and the Caribbean
        
        Clinical Features
        
        Skin rash (skin infiltration)
        
        Generalized lymphadenopathy
        
        Hepatosplenomegaly
        
        Lytic Punched Out Bone Lesions
        
        BONE PAIN
        All affect the bone, so how can you tell them apart?
        
        Adult T cell Lymphoma
        
        Multiple Myeloma
        
        Ewing sarcoma
        
        Chronic Osteomyelitis
        
        Prostatic Carcinoma
        
        Osteoid Osteoma
        
        Paget Disease of the bone
        
        Osteosarcoma
        
        Eosinophilic Granuloma
        
        Hand-Schuller-Christian Disease
        
        Letterer-Siwe Disease
        
        1. ATLL
        
        Lytic Punched-Out Bone Lesions
        
        RANK-R activation on osteoclast
        
        :arrow_up: Carbonic Anhydrase
        
        Lymphadenopathy
        
        Hepatomegaly
        
        (+) Rash
        
        2. Multiple Myeloma
        
        Lytic Punched-Out Bone Lesions
        
        RANK-R activation on osteoclast
        
        :arrow_up: Carbonic Anhydrase
        
        Proteinuria
        
        Amyloidosis (M-spike)
        
        Vertebra and skull
        
        (-) Rash
        
        3. Ewing Sarcoma
        
        4. Chronic Osteomyelitis
        
        5. Prostatic Carcinoma
        
        Prostatic Carcinoma is #1 cause of malignant bone cancer of all types
        
        Vertebra
        
        Tumor w/ adjacent sclerosis due to osteoblast activation
        
        (-) Rash
        
        6. Osteoid Osteoma
        
        7. Paget Disease of Bone
        
        8. Osteosarcoma
        
        9. Eosinophilic Granuloma
        
        Bone Pain And Fever
        
        Chronic Osteomyelitis
        
        Adult T cell Lymphoma
        
        Multiple Myeloma
        
        Ewing sarcoma
        
        Punched Out Lytic Lesions
        
        ATLL
        
        Multiple Myeloma (skull)
        
        Hand-Schuller-Christian Disease
        
        Patholgic Fracture
        
        Osteosarcoma
        
        Eosinophilic Granuloma
      - Proliferation of B cells
        
        Mature B cells
        
        Tartrate-Resistant Acid Phosphatase TRAP (+)
        
        Hairy Cell Leukemia
        
        Hairy Cytoplasmic Processes
        
        Splenomegaly to accumulation of hairy cells in the red pulp
        
        Dry tap due to marrow fibrosis
        
        Management
        
        Cladribine
        
        Adenosine Deaminase Inhibitor; adenosine accumulates to toxic levels in neoplastic B-cells
        
        Naive B cells
        
        13q Deletion
        
        CD5
        
        CD20
        
        Chronic Lymphocytic Leukemia
        Most Common Leukemia Overall
        
        Smudge Cells on blood smear
        
        Hypogammaglobulinemia - no functioning B cells means that infection in the most common cause of death in CLL
        
        Autoimmune hemolytic anemia
        
        Naive B cells spread to Lymph Nodes
        
        Generalized Lymphadenopathy
        
        Small Lymphocytic Lymphoma
        
        Follicular Lymphoma
        
        Mantle Cell Lymphoma
        
        Marginal Zone Lymphoma
        
        Enlarging Lymph Node
        
        or
        
        Enlarging Spleen
        
        Diffuse Large B-Cell Lymphoma
- - - - Immunodeficiency
        
        :arrow_down: CD4+ and CD8+
        
        DiGeorge
        
        :arrow_down: CD4+
        
        HIV
      - Late Hypercortisolemia
        
        Exogenous Corticosteroids
        &
        Cushing Syndrome
        
        Cortisol causes the apoptosis of lymphocytes
      - Autoimmune Destruction
        
        Systemic Lupus Erythematosus
      - Whole Body Radiation
        
        Lymphocytes are highly sensitive to radiation
        
        Lymphopenia is the first change to emerge following whole body radiationtext
    - - Severe Infection
        
        Increased movement of neutrophils into tissues leads to decreased circulating neutrophils
      - Drug Toxicity
        
        Alkylating agents which damages stem cells
        
        Most severely affects neutrophils
        
        Rx with GM-CSF or G-CSF
  - - - Bacterial Infection & Tissue Necrosis
        
        Release of marginated pool and bone marrow neutrophils
        
        Decreased Fc Receptor (CD16) expression on immature Neutrophils
      - Disorders Leukocyte Adhesion
      - Early Hypercortisolemia
        
        Exogenous Corticosteroids & Cushing Syndrome
        
        Circulating neutrophils will increase as cortisol impairs neutrophil adhesion
        
        after starting a patient on Glucocorticoid treatment there will be an initial increase in neutrophils followed by a decrease as apoptosis begins
    - - Chronic Inflammation
        
        Infection
        
        SLE
        
        Malignancy
    - - Allergic Reactions
      - Parasitic Infections
      - Hodgkin Lymphoma
    - - Chronic Myeloid Leukemia
    - - :arrow_up: T cells
        
        Viral Infections
        :arrow_up: CD4+
        :arrow_up: CD8+
        
        Expansion of Paracortex in lymph node
        
        :arrow_up: Reactive CD8+
        
        Positive Monospot
        
        (+) IgM cross reactive antibodies
        
        EBV Infectious Mononucleosis
        
        Affects:
        
        Oropharynx --> pharyngitis
        
        Liver --> hepatitis --> hepatomegaly
        
        :arrow_down: B cells
        
        EBV binds using B-cell CD21
        
        Presents with:
        
        Generalized Lymphadenopathy due to T-cell hyperplasia
        
        Paracortex dilates in lymph node
        
        Splenomegaly due to T-cell hyperplasia
        
        In periarterial lymphatic sheath
        
        Risk of splenic rupture
        
        Rash if treated with ampicillin
        
        Complications
        
        Increased risk for B-Cell Lymphoma
        
        Negative Monospot
        
        (-) IgM cross reactive antibodies
        
        CMV Infectious Mononucleosis
      - :arrow_up: B and T Cells
        
        Bordetella Pertussis Infection
        
        B. pertussis releases lymphocytosis-promoting factor which blocks circulating lymphocytes from leaving the blood to enter the lymph node. The net number of lymphocytes isn't changed but the amount is the blood is higher. Similar to Neutrophil adhesion factor deficiency or hypercortisolemia
- - - - Proerythroblast
        
        Basophilic Erythroblast
        
        Polychromatic Erythroblast
        
        Orthochromatic erythroblast
        
        (Normoblast)
        
        Polychromatic Erythrocyte
        
        (Reticulocyte)
        
        Erythrocyte
      - Myeloblast
        
        Monoblast
        
        Monocyte
        
        Macrophages
        
        Myeloid Dendritic Cell
        
        Promonocyte
        
        B. promyelocyte
        APML t(15;17)
        
        B. myelocyte
        
        B. Metamyelocyte
        
        B. Band
        
        Basophil
        
        N. promyelocyte
        APML t(15;17)
        
        N. Myelocyte
        
        N. Metamyelocyte
        
        N. Band
        
        Neutrophil
        
        E. promyelocyte
        APML t(15;17)
        
        E. Myelocyte
        
        E. Metamyelocyte
        
        E. Band
        
        Eosinophil
      - Megakaryoblast
        
        Promegakaryocyte
        
        Megakaryocyte
        
        Platelets
      - Mast Cell
    - - Lymphoblast
        
        Prolymphocyte
        
        Small Lymphocyte
        
        Naive T cell
        CD4+ CD8+ TCR
        
        CD8+ T cell
        CD8+ TCR
        Binds MHC I
        
        Cytotoxic T cell
        
        1 more item...
        
        CD4+ T cell
        CD4+ TCR
        Binds MHCII
        
        Antigen Presenting Cells
        (B cells, Dendritic Cells, Macrophages)
        MHC II
        HLA DP, HLA-DQ, HLA-DR
        
        2 equal length chains (α & β)
        
        Present exogenously synthesized antigens
        
        Antigen loaded following release of invariant chain in an acidified endosome
        
        Associated with Invariant Chain
        
        Immature Naive B Cell
        
        Mature Naive B cell
        
        Activated (B) Plasma Cell
        
        3 more items...
        
        IgM
        
        IgD
        
        Natural Killer Cell
      - Lymphoid Dendritic Cell
- - - - IL-1
        :check: Th17
        :check: Fever
      - TNF-α
        :check: Endothelium
        :check: Granuloma
        :arrow_right: cachexia
      - IL-12
        :check: Th1
        :check: NK Cells
        :arrow_right: IFN-γ
      - IL-8
        Neutrophil recruitment