• Hematopoiesis occurs via a stepwise maturation of CD34+ hematopoietic stem cells
• Cells mature and are released from the bone marrow into the blood
• A normal WBC count is 5-10
• A low WBC <5 k is called leukopenia
• a high WBC >10 leukocytosis
• A low or high WBC count is usually due to a decrease or increase in one particular cell lineage

• A decreased number of circulating neutrophils

Causes

1. Drug toxicity (ex chemotherapy with alkylating agents)-Damage to stem cells results in decreased prod. of WBCs, esp. neutrophils
2. Severe infection (Ex gram (-) sepsis) increased movement of neutrophils into tissues results in decreased circulating neutrophils
3. GM-CSF or G-CSF may be used pharmacologically to boost granulocyte production, thereby decreasing risk of infection

• Decreased number of circulating lymphocytes
• Causes:
• Immunodef. (Digeorge or HIV)
• High cortisol state (ex exogenous corticosteroids or Cushing syndrome)- induces apoptosis of lymphocytes
• Autoimmune destruction (ex SLE)
• Whole body radiation- lymphocytes are highly sensitive radiation;lymphopenia is the earliest change to emerge after whole body radiation

• Increased circulating neutrophils

Causes:

• Bacterial infection or tissue necrosis-induces release of marginated pool and bone marrow neutrophils, including immatur forms (left shift); immature cells are char. by decreased Fc receptors (CD 16)
• High cortisol state-impairs leukocyte adhesion, leading to release of marginated pool of neutrophils

• increased circulating monocytes
• Cause

1. Chronic inflammatory states (ex autoimmune and infectious) and malignancy

• Increased circulating Eosinophils
• Causes

1. Allergic Reactions (type I hypersensitivity)
2. Parasitic infections
3. Hodgkin lymphoma

• Eosinophilia is driven by increased eosinophil chemotactic factor

• Refers to increased circulating basophils
• Classically seen in chronic myeloid leukemia (CML)

• Increased circulating lymphocytes
• Causes:
• Viral infections-T lymphocytes undergo hyperplasia in response to virally infected cells
• Bordetella pertussis infection-Bacteria produce lymphocytosis- promoting factor, which block circulting lymphocytes from leaving the blood to enter the lymph node

• EBV infection that results in a lymphocytic leukocytosis comprised of reactive CD8+ T cells; CMV is a less common cause
• EBV is transmitted by salivea "kissing disease" classically affects teenagers
• EBV primarily infects: oropharynx, resulting in pharyngitis
• Liver resulting in hepatitis w/ hepatomegaly and elevated liver enzymes
• B cells
• CD8+ T cell response leads to generalized lymphadeopathy (LAD) due to T-cell hyperplasia in the lymph node paracortex
• Splenomegaly due to T-cell hyperplasia in the periarterial lymphatic sheath (PALS)
• High WBC count w/ atypical lymphocytes (reactive CD8+T cells) in the blood
• The monospot test is used for screening

1. Detects IgM antibodies that cross-react w/ horse or sheep RBCs (heterophile Abs)
2. Usually turns positive w/i 1 week after infection
3. A negative monospot test suggests CMV as a possible cause of IM
4. Definitive diagnosis is made by serologic testing for the EBV viral capsid antigen

• Complications

1. Increased risk for splenic rupture (no contact sports for 1 year)
2. Rash if exposed to ampicillin
3. Dormancy of virus in B cells leads to increased risk for both recurrence and B-cell lymphoma, especially if immunodeficiency (ex HIV develops)

• Neoplastic prolif. of blasts; defines as the accumulation of >20% blasts in the bone marrow
• Increased blasts "crowd-out" normal hematopoiesis, resulting in an acute presentation w/ anemia (fatigue), thrombocytopenia (bleeding), or neutropenia (infection)
• blasts usually enter the blood stream, resulting in a high WBC count.
• Blasts are large, immature cells, often w/ punched out nucleoli
• Acute leukemia is subdivided into acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) based on the phenotype of the blasts

• NEoplastic accumulation of lymphoblasts >20 % in the bone marrow
• Lymphoblasts are char. by postitve nuclear staining for TdT, a DNA polymerase
• TdT is absent in myeloid blasts and mature lymphocytes
• Most commonly arises in children; associated w/ Down Syndroe (usually arises after the age of 5)
• Sublclassified into B-ALL and T-ALL base on surface markers

• Most common type of ALL
• usually char. by lymphoblasts (TdT+) that express CD10, CD19, and CD20
• Excellent response to chemo; req. prophylaxis to scrotum and CSF
• Prognosis is based on cytogenetic abnormalities
• t (12;21) has a good prognosis; more commonly seen in kids
• t (9;22) has a poor prognosis; more commonly seen in adults (Philadelphia+ ALL)
• [image]

• Characterized by lymphoblasts (TdT+) that express markers ranging from CD2 to CD8 (ex CD3, CCD4, CD7).  The blasts do not express CD10
• Usually presents in teenagers as a mediastinal (thymic) mass call acute lymphoblastic lymphoma because the malignant cells form a mass

Acute Myeloid Leukemia

• Neoplastic accumulation of myeloblasts >20% in the bone marrow
• Myeloblasts are usually characterized by posititve cytoplasmic staining for myeloperoxidase (MPO)
• cystal aggregates of MPO may be seen as Auer rods
• Most commonly arises in older aults (avg age 50-60 years)
• Subclassified base on cytogenetic abnormalities, lineage of myeloblasts, and surface markers

• Char. by t (15;17), which involves translocation of the retinoid acid receptor (RAR) on chromosome 17 to chromosome 15; RAR disruption blocks maturation and promyelocytes (blasts) accumulate.
• Abnormal promyelocytes contain numerous primary granules that increase the risk for DIC
• treatment is with all-trans retinoic acid (ATRA, a vitamin A derivative), which binds the altered receptor and causes the blasts to mature (and eventually die)

• Proliferation of monoblasts; usually lack MPO
• Blasts char. infiltrate gums

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

• May also arise from pre-existing dysplasia (myelodysplastic syndromes) especially w/ prior exposure to alkylating agents or radiotherapy
• Myelodysplastic syndromes usually present w/ cytopenias, hyperpercellular bone marrow, abnormal maturation of cells,a nd increased blasts <20%
• Most patients die from infarction or bleeding, though some progress to acute leukemia

• Neoplastic proliferation of mature circulating lymphocytes; char. by a high WBC count
• Usually insidious in onset and seen in lder adults

• Neoplastic proliferation of naive B cells that co-express CD5 and CD20; most common leukemia overall
• Increased lymphocytes and smudge cells are seen on blood smear
• involvement of lymph nodes leads to generalized lymphadenopathy and is called small lymphocytic lymphoma
• Complications include:

1. Hypogammaglobulinemia-infection is the most common cause of death in CLL
2. Autoimmune hemolytic anemia
3. Transformation to diffuse large B-cell lymphoma (Richter transformation)-Marked clinically by an enlarging lymph node or spleen

• Neoplastic proliferation of mature B cells char. by hairy cytoplasmic processes
• Cells are positive for tartrate-resistant acid phosphatase (TRAP)
• Clin. features inc. splenomegaly (due to accum. of hair cells in red pulp) and dry tap on bone marrow aspiration (due to marrow fibrosis).
• Lymphadenopathy is usually absent

[image]

• Excellent response ot 2-CDA (cladribine), and adenosine deaminase inhibitor; adenosine accumulates to toxic levels in neoplastic B cells.

Acute T-Cell leukemia/Lymphoma (ATLL)

• Neoplastic proliferation of mature CD4+ t cells
• Associated w/ HTLV-1; most commoly seen in Japan and the Caribbean
• Clinical features include rash (skin infiltration), gen. lymphadenopathy w/ hepatospenomegaly, and lytic (punched-out) bone lesions w/ hypercalcemia

• Neoplastic prolif. of mature CD4+ T cells that infiltrate the skin, prod. localized skin rash, plaques, and nodules/  Aggregates of neoplastic cells in the epidermis are called Pautrier microabcesses
• Cell can spread to involve the blood, producing Sezary syndrome
• Char. lymphocytes w/ cerebriform nuclei
• [image]

• Basic Principles
• Neoplastic proliferation of mature cells of myeloid lineage; disease of late adulthood (avg age is 50-60 years)
• Results in high WBC count w/ hypercellular bone marrow
• Cells of all myeloid lineages are increased; classified based on the dominant myeloid cell produced.
• Complications include
• Increased risk for hyperuricemia and gout due to high turnover of cells
• progression to marrow fibrosis or transformation to acute leukemia

• neoplastic proliferation of mature myeloid cells, esp. granuloctes and their precursors; basophils are char. increased
• Driven by t (9;22) Philadelphia chromosome which gen a BCR-ABL fusion protein with increased tyrosine kinase activity
• First line treatment is imatinib, which blocks tyrosine kinase activity
• Splenomegaly is common.  Enlarging spleen suggests accelerated phase of disease transformation to acute leukemia usually follows shortly therafter
• Can transform to AML (2/3) of cases or ALL (1/3) sine mutation is in a pluripotent stem cell
• CML is dist. from a leukemoid rxn (reactive neutrophilic leukocytosis by

1. Negative leukocyte alkaline phosphatase (LAP) stain (granulocytes in a leukemoid reaction are LAP positive)
2. Increased basophils (Absent w/ leukemoid reaction)
3. t9;22 absent in leukemoid reaction

• Neoplastic proliferation of mature myeloid cells, especially RBCs
• Granulocytes and platelets are also increased
• Associated w/ JAK2 kinase mutation
• Clinical symptoms are mostly due to hyperviscosity of blood

1. Blurry vision and headache
2. increased risk of venous thrombosis (Ex hepatic vein, portal vein, and dural sinus)
3. Flushed face due to congestion (plethora)
4. Itchin, especially after bathing (due to histamine release from increased mast cells)
5. Treatment is phblebotomoy; second-line therapy is hydroxyurea
6. w/o treatment, death usually occurs w/i one year
7. PV must be distinguished from reactive polycythemia

• In PV, EPO levels are decreased, and SaO2 is normal
• In reactive polycythemia due to high altitude or lung disease, SaO2 is low, and EPO is increased
• In reactive polycythemia due to ectopic EPO prod. from renal cell carcinoma, EPO is high, and SaO2 is normal

• Neoplastic proliferation of mature myeloid cells, especially platelets
• RBCs and granulocytes are also increased
• Associated w/ JAK2 kinase mutation
• Symptoms are related to an increased risk of bleeding and/or thrombosis
• Rarely progresses to marrow fibrosis or acute leukemia
• No sig. risk for hyperuricemia or gout

Myelofibrosis

• Neoplastic proliferation of mature myeloid cells, esp. megakaryocytes
• Associated w/ JAK2 kinase mutation (50% of cases)
• Megakaryocytes produce excess platelet-derived growth factor (PDGF) causing marrow fibrosis
• Clinical features include:

1. Splenomegaly due to extramedullary hematopoiesis
2. Leukoerythroblastic smear (tear-drop RBCs, nucleated RBCs, and immature granulocytes)
3. Increased risk of infection, thrombosis and bleeding

• LAD refers to enlarged lymph nodes
• Painful lAD is usually seen in lymph nodes that are draining a region of acute infection (acute lymphadenitis)
• Painless LAD can be seen w/ chronic inflammation (chronic lymphadenitis), metastatic carcinoma, or lymphoma
• In inflammation, lymph node enlargement is due to hyperplasia of particular regions of the lymph node
• Follicular Hyperplasia (B-cell region) is seen with rheumatoid arthritis and early stages of HIV infection, for ex
• Paracortex hyperplasia (T-cell region) is seen w/ viral infections (ex infectious mononucleosis)
• Hyperplasia of sinus histiocytoses is seen in lymph nodes that are draining a tissue w/ cancer

• Neoplastic proliferation of lymphoid cells that forms a mass; may arise in a lymph node or in extranodal tissue
• Divided into non-Hodgkin lymphoma (NHL, 60%) and Hodgkin lymphoma (HL, 40%)
• NHL is further classified base on cell type (ex B versus T), cell size, pattern of cell growth, expression of surface markers, and cytogenetic translocations
• Small B cells-follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma (ie CLL) cells that involve tissue
• Intermediate-sized B cells- Burkitt lymphoma
• Large B cells- diffuse large B-cell lymphoma

• Neoplastic proliferation of small B cells (CD20+) that form follicle-like nodules
• Clinically presents in late adulthood w/ painless lymphadenopathy
• Driven by t (14;18)
• BCL2 on chromosome 18 translocates to teh Ig heavy chain locus on chromosome 14
• results in overexpression of Bcl2, which inhibits apoptosis
• Treatment is reserved for patients who are symptomatic and involves low-dose chemotherapy or rituximab (anti-CD20 antibody)
• Progression to diffuse large B-cell lymphoma is an important complication; presents as an enlarging lymph node
• Follicular lymphoma is distinguished from reactive follicular hyperplasia by:

1. Disruption of normal lymph node architecture (maintained in follicular hyperplasia)
2. Lack of tingible body macrophages in germinal centers (tingible body macrophages are present in follicular hyperplasia
3. Bcl2 expression in follicles (not expressed in follicular hyperplasia
4. Monoclonality (follicular hyperplasia is polyclonal)

• Neoplastic proliferation of small B cells (CD20+) that expands the mantle zone
• Clinically presents in late adulthood w/ painless lymphadenopathy
• Driven by 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 the cell cycle, facilitating neoplastic proliferation

• Neoplastic proliferation of small B cells CD20+ that expands teh marginal zone
• Associated w/ chronic inflammatory states such as Hashimoto thyroiditis, Sjogren syndrome, and H. pylorid gastritis
• The marginal zone is formed by post-germinal center B cells
• MALToma is marginal zone lymphoma in mucosal sites
• Gastric MALToma may regress with treatment of H pylori

• Neoplastic proliferation of intermediate-sized B cells (CD20+); associated w/ HBV
• classically presents as an extranodal mass in a child or young adult
• African form usually involves the jaw
• sporadic form usually involves the abdomen
• Driven by translocation of c-myc (chromosome 8)
• T (8;14) is most common, resulting in translocation of c-myc to the Ig heavy chain locus on chromosome 14
• Overexpression of c-myc oncogene promotes cell growth
• Char. by high mitotic index and "starry-sky" appearance on microscopy

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

• Neoplastic proliferation of Reed-Sternberg (RS) cells, which are large B cells with multilobed nuclei and prom. nucleoli (owl-eyed nuclei); clasically positive for CD15 and CD30
• RS cells secrete cytokines
• Occaisonally result in B symptoms (fever, chills, and night sweats)
• Attract reactive lymphocytes, plasma cells, macrophages, and eosinophils
• May lead to fibrosis
• Reactive inflammatory cells make up a bulk of the tumor and form the basis for classification of HL.  Subtypes include

1. Nodular sclerosis
2. Lymphocyte-rich
3. Mixed Cellularity
4. Lymphocyte-depleted
5. Nodular sclerosis is the most common type of HL (70% of all cases)

• Classic presentation is an enlarging cervical or mediastinal lymph node in a young adult, usually female
• Lymph node is divided by bands of sclerosis; RS cells are present in lake-like spaces (lacunar cells, fig 6.19B
• Important considerations regarding other subtypes of HL

1. Lymphocyte-rich has the best prognosis of all types
2. Mixed cellularity is often associated w/ abundant eosinophils (RS cells prod. IL-5)
3. Lymphocyte-depleted is the most aggressive of all types; usually seen in the elderly and HIV-posititve individuals

• Malignant proliferation of plasma cells in the bone marrow
• Most common primary malignancy of bone; metastatic cancer, however, is the most common malignant lesion of bone overall
• High serum IL-6 is sometimes present; stimulates plasma cell growth and immunoglobulin production

Clin. features include:

1. Bone pair w/ hypercalcemia-neoplastic plasma cells activate the RANK receptor on osteoclasts, leading to bone destruction.  Lytic "punched-out" skeletal lesions are seen on x-ray, especially in the vertebrae and skull; increased risk for fracture
2. Elevated serum protein-neoplastic plasma cells prod. immunoglobulin; M spike is present on serum protein electrophoresis (SPEP), most commonlyd due to monoclonal IgG or IgA
3. Increased risk of infection Monoclonal antibody lacks antigenic diversity; infection is the most common cause of death in multiple myeloma
4. Rouleaux formation of RBCs on blood smear-increased serum protein decreases charge between RBCs
5. Primary AL amyloidosis-Free Light chains circulate  in serum and deposit on tissues
6. Proteinuria- Free light chain is excreted in the urine as Bence Jones protein; deposition in kidney tubules leads to risk for for renal failure (myeloma kidney)

• Increased serum protein w/ M spike on SPEP; other features of multiple myeloma are absent (ex no lytic bone lesions, hypercalcemia, AL amyloid, or bence jones proteinuria)
• COmmon in elderly (seen in 5% of 70 year old individuals); 1% of patients w/ MGUS develop multiple myeloma each year

• B-cell lymphoma w/ monoclonal IgM production
• Clinical features include:

1. Generalized lymphadenopathy; lytic bone lesions are absent
2. increased serum protein w/ M spike (comprise of IgM)
3. Visual and neurologic deficits (ex retinal hemorrhage or stroke)- IgM (large pentamer) causes serum hyperviscosity
4. Bleeding-Viscous serum results in defective platelet aggregation
5. Acute complications are treated w/ plasmapheresis, which removes IgM from the serum

• Langerhans cells are specialized dendritic cells found pred. in the skin.
• Derived from bone marrow monocytes
• Present antigen to naive T cells
• Langerhans cell histiocytosis is a neoplastic proliferation of Langerhans cells
• Characteristic Birbeck (tennis racket) granules are seen on electron microscopy cells are CD1a+ and S100+ by immunohistochemistry

• Malignant proliferation of Langerhans cells
• Classic presentation is skin rash and cystic skeletal defects in an infant <2 years old
• multiple organs may be involved; rapidly fatal

• Benign proliferation of Langerhans cells in bone
• Classic presentation is pathologic fracture in an adolescent; skin is not involved
• Biopsy shows Langerhans cells with mixed inflammatory cells, including numerous eosinophils

• Malignant proliferation of Langerhans cells
• Classic presentation is scalp rash, lytic skull defects, diabetes insipidus, and exophthalamos in a child