WBC disorders

Hematopoiesis

• Myeloid stem cells
• → AML

• Lymphoid stem cells
• → ALL, CL

WBC count <5,000

• Usually due to one cell type:
• 1. Neutropenia
• -Cuase:drug toxicity - chemotherapy; severe infection
• -Tx: GM-CSF or G-CSF (to boost granulocyte production)

• 2. Lymphopenia
• -Cause: immunodeficiency (DeGeorge, HIV); corticosteroids/cushing syndrome; autoimmune destruction (SLE); whole body radiation

• WBC > 10,000
• Also usually due to one cell type:
• 1. Neutrophilic leukocytosis:
• -bacterial infection, tissue necrosis; high cortisol state

• 2. Monocytosis
• -chronic inflammatory states, malignancy

• 3. Eosinophilia:
• -allergic reactions (type I hypersensitivity), parasitic infections, Hodgkin lymphoma

• 4. Basophilia
• -chronic myeloid leukemia

• 5. Lymphocytic leukemia
• -viral infection; Bordetella pertussis infection

• Cause:
• -EBV infection → lymphocytic leukocytosis (reactive CD8+ T cells)
• -CMV is less common cause

• Effects of EBV:
• -Oropharynx → pharyngitis
• -liver → hepatitis, hepatomegaly, ↑ liver enzymes
• -B cells

• T cell response:
• -Generalized lymphadenopathy
• -Splenomegaly
• -↑ WBC count with atypical lymphocytes

• Complications:
• -splenic rupture
• -rash if exposed to ampicillin
• -Recurrence, possibly B-cell lymphoma (especially if immunodeficient)

• Monospot test:
• -Detects IgM antibodies
• -Usually turns positive after 1 week
• -Negative monospot → possible CMV

• Proliferation of blasts - > 20% blast in bone marrow defines acute leukemia
• 

• Presentation:
• -anemia (fatigue)
• -thrombocytopenia (bleeding)
• -neutropenia (infection)

• Types:
• -Acute lymphoblastic leukemia (ALL)
• -Acute myelogenous leukemia (AML)

• Lymphoblasts (>20%) in the bone marrow
• Positive nuclear staining for TdT (DNA polymerase)
• Childhood neoplasia (after age 5)
• Associated with Down syndrome
• Subclass: B-ALL and T-ALL

• Most common type
• Lymphoblasts (TdT+) that express CD10, CD19,CD20
• Prognosis based on cytogenetics:
• -t(12:21) has good prognosis - more common in children
• -t(9:22) has poor prognosis - more common in adults ("Philadelphia+ ALL)
• Tx: Excellent response to chemotherapy

• Lymphoblasts (TdT+) that express CD2-CD8 (no CD10)
• Presentation: Teenagers, mediastinal (thymic) mass
• aka acute lymphoblastic lymphoma bc cells form a mass
• *T-ALL, Teenagers, Thymic mass

• Accumulation of myeloblasts (>20%)
• Positive cytoplasmic staining for myeloperoxidase (MPO) - seen as Auer rods
• 
• Presentation: Adults (50-60yrs)
• Subclass: cytogenetic abnormalities, lineage of myeloblasts, surface markers
•      -Acute Promyelocytic Leukemia (APL)
•      -Acute Monocytic Leukemia
•      -Acute Megakaryoblastic Leukemia
• Pre-existing dysplasia: myelodysplastic syndrome

Can progress to AML, especially with exposure to alkylating agents or radiotherapy

• Presentation:
• -cytopenias
• -hypercellular bone marrow
• -abnormal maturation of cells
• -increased blasts (<20%)

*Most die from infection or bleeding; some progress to acute leukemia

• -t(15:17) - retinoic acid receptor (RAR) on chrom 17 → chrom 15
• -Increase risk for DIC
• Tx:
• -all-trans-retinoic acid (ATRA) - a vitamin A derivative (causes blasts to mature)

• Proliferation of monoblasts
• usually lack MPO
• Blasts infiltrate gums

• Proliferation of megakaryoblasts
• Lack MPO
• Associated with Down syndrome (arises before the age of 5)

• Proliferation of mature circulating lymphocytes
• High WBC count
• Insideous in onset
• Older adults
• Types:
•      -Chronic Lymphocytic Leukemia (ALL)
•      -Hairy Cell Leukemia
•      -Adult T-Cell Leukemia/Lymphoma (ATLL)
•      -Mycosis Fungoides

• Proliferation of naïve B cells that co-express CD5 and CD20
• Most common leukemia overall

• Blood smear: lymphoctes, smudge cells
• 

Can involve lymph nodes → generalized lymphadenopathy ("small lymphocytic lymphoma")

• Complications:
• -Hypogammaglobulinemia
• -Autoimmune hemolytic anemia
• -Transform to diffuse large B-cell lymphoma (Richter transformation)

• Proliferation of mature B cells - hairy cytoplasmic processes
• Positive for tartrate-resistant acid phosphatase (TRAP)
• Features: splenomegaly; "dry tap" on bone marrow aspiration
• Tx: 2-CDA (cladribine) (an adenosine deaminase inhibitor)

• -Proliferation of mature CD4+ T cells
• -Associated with HTLV-1 (Japan, Caribbean)

• Features:
• -rash
• -generalized lymphadenopathy
• -hepatosplenomegaly
• -lytic (punched-out) bone lesions with hypercalcemia

• Proliferation of mature CD4+ T cells that infiltrate the skin → localized rash, plaques, nodules
• "Pautrier microabscesses"

• *Cells can spread to involve the blood → Sezary syndrome
• -Sezary cells: cerebriform nuclei on blood smear (lobes)

• Mature cells of myeloid lineage
• Epidemiology: late adulthood (50-60yrs)
• Presentation: high WBC count; hypercellular bone marrow; ↑ granuclocytes
• Complications: hyperuricemia, gout; progression to marrow fibrosis or transform to acute leukemia
• Types:
• -Chronic myeloid leukemia
• -Polycythemia vera
• -Essential thrombocythemia
• -Myelofibrosis

• Proliferation of myeloid cells, especially granulocytes and their precursors
• Basophils are characteristically increased
• t(9:22) (Philadelphia chromosome) → BCR-ABL fusion protein (↑ tyrosine kinase activity)
• Splenomegaly is common → suggests accelerated phase of disease
• Tx: imatinib (blocks tyrosine kinase)
• Complications: transform to AML (2/3 of cases) or ALL (1/3 of cases)

• CML:
• -Negative leukocyte alkaline phosphatease (LAP) stain
• -Increased basophils
• -t(9:22)

• Proliferation of mature myeloid cells, especially RBCs (↑ granulocytes, ↑ platelets)
• JAK2 kinase mutation

• Clinical presentation: hyperviscosity of blood...
• -Blurry vision and headache
• -Increased risk of venous thrombosis (hepatic vein, portal vein, dural sinus)
• -Flushed face due to congestion
• -Itching

Tx: phlebotomy; hydroxyurea

• Distinguish from reactive polycythemia:
• -PV → EPO levels are decreased, Sa_O2 is normal
• -Reactive polycythemia (high altitude, lung disease) → Sa_O2 is decreased, EPO is high
• -Reactive polycythemia (ectopic EPO production from RCC) → both EPO and Sa_O2 are high

• Proliferation of mature myeloid cells, especially platelets (↑ RBCs, ↑ granulocytes)
• *JAK2 kinase mutation

• Sx: increased risk of bleeding and/or thrombosis
• -rarely progresses to marrow fibrosis or acute leukemia
• -No significant risk for hyperuricemia or gout

• Proliferation of mature myeloid cells, especially megakaryocytes
• *JAK2 kinase mutation (50% of cases)
• Megakaryocytes → excess platelet-derived growth factor (PDGF) causing marrow fibrosis
• Clinical feature:
• -Splenomegaly (extramedullary hematopoiesis)
• -Leukoerythroblastic smear
• -Increased risk of infection, thrombosis, bleeding

• Painful LAD: acute infection (acute lymphadenitis)
• Painless LAD: chronic inflammation, metastatic carcinoma, lymphoma
•       → hyperplasia of particular regions:
• 1. Follicular hyperplasia (B-cell region) seen in RA, early HIV infections
• 2. Paracortex hyperplasia (T-cell region) seen in viral infections (mono)
• 3. Hyperplasia of sinus histiocytes seen in LN that are draining cancer

• Proliferation of lymphoid cells that form a mass; within LN or extranodul tissue
• non-Hodgkin (NHL, 60%) vs Hodgkin lymphoma (HL, 40%)

• NHL subclasses:
• -Small B cells: follicular, mantle, marginal, small lymphocytic lymphoma (CLL cells that involve tissue)
• -Intermediate-sized B cells: Burkitt lymphoma
• -Large B cells: diffuse large B-cell lymphoma

• Malignant cells: Lymphoid cells
• Composition of mass: lymphoid cells
• Clinical presentation: Painless LAD, usually arises in late adulthood
• Spread: diffuse; often extranodal
• Staging: limited importance
• Leukemic phase: occurs

• Malignant cells: Reed-Sternberg cells
• Composition of mass: Predominantly reactive cells (inflammatory cells and fibrosis)
• Clinical presentation: Painless LAD occasionally with 'B' symptoms; young adults
• Spread: Contiguous; rarely extranodal
• Staging: guides therapy; radiation is mainstay of tx
• Leukemic phase: Does NOT occur

• Neoplastic proliferation of small B cells (CD20+)
• Presentation: late adulthood, painless LAD

• t(14:18) - BCL2 on chromosome 18 translocates to the Ig heavy chain on chromosome 14
• → overexpression of Bcl2, which inhibits apoptosis

• Treatment: only when symptomatic, low dose chemo or rituximab (anti-CD20 antibody)
• Complication: preogression to diffuse large B-cell lymphoma

• Follicular lymphoma vs reactive follicular hyperplasia:
• -disruption of normal LN architecture
• -lack of tingible body macrophages in germinal centers
• -Bcl2 expression in follicles
• -Monoclonality

Neoplasatic proliferation of small B cells (CD20+) that expands the mantle zone

Presentation: late adulthood, painless LAD

• t(11:14)
• -Cyclin D1 gene on chromosome 11 translocates to Ig heavy chain locus on chromosome 14
• -Overexpression of cyclin D1 promotes G1/S transition in cell cycle

Neoplasatic proliferation of small B cells (CD20+) that expands the marginal zone

• Associated with chronic inflammatory states:
• -Hashimoto thyroiditis
• -Sjögren syndrome
• -H pylori gastritis

MALToma is marginal zone lymphoma in mucosal sites

• Neoplastic proliferation of intermediate-size B cells (CD20+)
• Associated with EBV
• Presentation: extranodal mass in child or young adult (African → jaw; sporadic → abdomen)
• t(8:14) → c-myc on chromosome 8 to the Ig heavy chain locus on chromosome 14
• →overexpression of c-myc oncogene promotes cell growth
• "Starry-sky" appearance

• Neoplastic proliferation of large B cells (CD20+) that grow diffusely in sheets
• Most common form of NHL
• Clinically aggressive (high-grade)
• Sporadically or from transformation of a low-grade lymphoma (follicular lymphoma)
• Presentation: late adulthood as an enlarging lymph node or extranodal mass

• Neoplastic proliferation of Reed-Sternberg (RS) cells; large B cells with multilobed nuclei
• Prominant nucleoli ('owl-eyed nuclei')
• CD15 and CD30 positive

• RS cells: secrete cytokines
• -"B" symptoms (fever, chills, night sweats)
• -Attract reactive lymphocytes, plasma cells, macrophages, eosinophils
• -May lead to fibrosis

• HL subtypes: based on reactive inflammatory cells (make up bulk of the tumor)
• -Nodular sclerosis (most common)
• -Lymphocyte-rich (best prognosis)
• -Mixed cellularity (abundant eosinophils)
• -Lymphocyte-depleted (most aggressive; seen in elderly and HIV-positive)

• Myltiple myeloma
• Monoclonal gammopathy of undetermined significance (MGUS)
• Waldenström macroglobulinemia

• Malignant proliferation of plasma cells in the bone marrow
• -Most common primary malignancy of bone
• -High serum IL-6 is sometimes present (stimulates plasma cell growth and Ig production)

• Clinical features:
• -Bone pain with hypercalcemia (punched-out lesions, especially skull)
• -Elevated serum protein (M spike; IgG or IgA most commonly)
• -Increased risk of infection (antibodies lack antigenic diversity)
• -Rouleaux formation of RBCs on smear
• -Primary AL amyloidosis
• -Proteinuria

• Increased serum protein with M spike
• other features of multiple myeloma are absent
• Common in elderly (5% of 70 year olds)
• 1% of pts with MGUS develop multiple myeloma each year

B-cell lymphoma with monoclonal IgM production

• Clinical features:
• -Generalized LAD (lytic bone lesions are absent)
• -Increased serum protein with M spike
• -Visual and neurologic deficits - IgM causes serum hyperviscosity
• -Bleeding

Tx: acute complications are treated with plasmapheresis, which removes IgM from the serum

• Langerhans cells are specialized dendritic cells, found predominantly in the skin
• -from bone marrow monocytes
• -Present antigen to naive T cells

• Neoplastic proliferation of langerhans cells:
• -Birbeck (tennis racket) granules are seen on em
• -CD1a+ and S100+ by immunohistochemistry

• Types:
• -Letterer-Siwe disease
• -Eosinophilic granuloma
• -Hand-Schuller-Christian disease

• Malignant proliferation of Langerhans cells
• Presentation: skin rash, cystic skeletal defects in an infant (<2 years old)
• Multiple organs may be involved
• rapidly fatal

• Benign proliferation of Langerhans cells in bones
• Presentation: pathologic fracture in an adolescent
• Skin is not involved
• Bx: Langerhans cells with mixed inflammatory cells, eosinophils

• Malignant proliferation of Langerhans cells
• Presentation: scalp rash, lytic skull defects, diabetes insipidus, exopthalmos
• Children (>3 years old)