White Blood Cell Disorders Flashcards
1
Q
Basic Principles
A
- hematopoiesis occurs in 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 approximately 5-10 K/mL
- low WBC is called leukopenia (10)
2
Q
Leukopenia (neutropenia)
A
- neutropenia refers to a decreased number of circulating neutrophils
- drug toxicity: damage to stem cells results in decreased production of WBCs, especially neutrophils
- severe infection: increased movement of neutrophils into tissues results in decreased circulating neutrophils
- as a treatment, GM-CSF or G-CSF may be used to boost granulocyte production, thereby decreasing risk of infection in neutropenic pts
3
Q
Leukopenia (lymphopenia)
A
- refers to a decreased number of circulating lymphocytes
- immunodeficiency: (e.g. DiGeorge syndrome or HIV)
- high cortisol state (e.g. exogenous corticosteroids or Cushing syndrome): induces apoptosis of lymphocytes
- autoimmune destruction (e.g. systemic lupus erythematosus)
- whole body radiation: lymphocytes are highly sensitive to radiation; lymphopenia is the earliest change to emerge after whole body radiation
4
Q
Neutrophilic Leukocytosis
A
- refers to increased circulating neutrophils
- bacterial infection or tissue necrosis: induces release of marginated pool and bone marrow neutrophils, including immature forms (left shift); immature cells are characterized by decreased Fc receptors (CD16)
- high cortisol state: impairs leukocyte adhesion, leading to release of marginated pool of neutrophils
5
Q
Monocytosis
A
- refers to increased circulating monocytes
- causes include chronic inflammatory states (e.g. autoimmune and infectious) and malignancy
6
Q
Eosinophilia
A
- refers to increased circulating eosinophils
- causes include allergic reactions (type I hypersensitivity), parasitic infections, and Hodgkin lymphoma
- eosinophilia is driven by increased eosinophil chemotactic factor
7
Q
Basophilia
A
- refers to increased circulating basophils
- classically seen in chronic myeloid leukemia
8
Q
Lymphocytic Leukocytosis
A
- refers to increased circulating lymphocytes
- viral infections: T lymphocytes undergo hyperplasia in response to virally infected cells
- Bordetella pertussis infection: bacteria produce lymphocytosis-promoting factor, which blocks circulating lymphocytes from leaving the blood to enter the lymph nodes
9
Q
Infectious Mononucleosis (IM)
A
- EBV infection that results in a lymphocytic leukocytosis comprised of reacive CD8+ T cells
- CMV is a less common cause
- primarily infects oropharynx, resulting in pharyngitis; liver, resulting in hepatitis with hepatomegaly and elevated liver enzymes; B cells
- CD8+ T cell response leads to generalized lymphadenopathy due to T-cell hyperplasia in the lymph nodes; splenomegaly due to T-cell hyperplasia in the pariarterial lymphatic sheath (PALS); high WBC count with atypical lymphocytes (reactive CD8+ T cells) in the blood
10
Q
Monospot Test for Mononucleosis
A
- detects IgM antibodies that cross-react with horse or sheep red blood cells (heterophile antibodies)
- usually turns positive within 1 week after infection
- a negative monospot test suggests CMV as a possible cause of IM
- definitive diagnosis is made by serologic testing for the EBV viral capsid antigen
11
Q
Complications of Mononucleosis
A
- increased risk for splenic rupture; patients are generally advised to avoid contact sports for 1 month
- rash if exposed to ampicillin
- dormancy of virus in B cells leads to increased risk for both recurrence and B-cell lymphoma, especially if immunodeficiency (e.g. HIV) develops
12
Q
Acute Leukemia (Basic Principles)
A
- neoplastic proliferation of blasts; defined as the accumulation of >20% blasts in the bone marrow
- increased blasts “crowd-out” normal hematopoiesis, resulting in an “acute” presentation with anemia (fatigue), thrombocytopenia (bleeding), or neutropenia (infection)
- blasts usually enter the blood stream, resulting in high WBC count
- blasts are large, immature cells, often with punched out nucleoli
- acute leukemia is subdivided into acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) based on the phenotype of the blasts
13
Q
Acute Lymphoblastic Leukemia (ALL)
A
- neoplastic accumulation of lymphoblasts (>20%) in the bone marrow
- lymphoblasts are characterized by positive nuclear staining for TdT, a DNA polymerase
- TdT is absent in myeloid blasts and mature lymphocytes
- most commonly arises in children; associated with Down syndrome (usually arises after the age of 5 years)
- subclassified into B-ALL and T-ALL base don surface markers
14
Q
B-ALL
A
- most common type of ALL
- usually characterized by lymphoblasts (TdT+) that express CD10, CD19, and CD20
- excellent response to chemotherapy; requires prophylaxis to scrotum and CSF
- prognosis is based on cytogenetic abnormalities
- t(12;21) has a good prognosis; more commonly seen in children
- t(9;22) has a poor prognosis; more commonly seen in adults (Philadelphia+ALL)
15
Q
T-ALL
A
- characterized by lymphoblasts (TdT+) that express markers ranging from CD2 to CD8 (e.g. CD3, CD4, CD7)
- the blasts do not express CD10
- usually presents in teenagers as a mediastinal (thymic) mass (called acute lymphoblastic lymphoma because the malignant cells form a mass)
16
Q
Acute Myeloid Leukemia
A
- neoplastic accumulation of immature myeloid cells (>20%) in the bone marrow
- myeloblasts are usually characterized by positive cytoplasmic staining for myeloperoxidase (MPO)
- most commonly arises in older adults (avg 50-60 yrs)
- subclassification based on cytogenetic abnormalities, lineage of immature myeloid cells, and surface markers
- AML may also arise from pre-existing dysplasia (myelodysplastic syndromes), especially with prior exposure to alkylating agents or radiotherapy
- myelodysplastic syndromes usually present with cytopenias, hypercellular bone marrow, abnormal maturation of cells, and increased blasts (<20%)
- most patients die from infection or bleeding, though some progress to acute leukemia
17
Q
Acute Promyelocytic Leukemia (APL)
A
- characterized by t(15:17), which involves translocation of the retinoic 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)
18
Q
Acute Monocytic Leukemia
A
- proliferation of monoblasts; usually lack MPO
- blasts characterstically infiltrate gums
19
Q
Acute Megakaryoblastic Leukemia
A
- proliferation of megakaryoblasts; lack MPO
- associated with Down syndrome (usually arises before the age of 5)
20
Q
Chronic Leukemia (Basic Principles)
A
- neoplastic proliferation of mature circulating lymphocytes; characterized by a high WBC count
- usually insidious in onset and seen in older adults
21
Q
Chronic Lymphocytic Leukemia (CLL)
A
- neoplastic proliferation of naive B cells that co-express CD5 and CD20
- increased lymphocytes and smudge cells are seen on blood smear
- involvement of lymph nodes leads to generalized lymphadenopathy and is called small lymphocytic lymphoma
22
Q
Complications of CLL
A
- hypogammaglobulinemia: infection is the most common cause of death in CLL
- autoimmune hemolytic anemia
- transformation to diffuse large B-cell lymphoma (Richter transformation) - marked clinically by an enlarging lymph node or spleen
23
Q
Hairy Cell Leukemia
A
- neoplastic proliferation of mature B cells characterized by hairy cytoplasmic processes
- cells are positive for tartrate-resistant acid phosphatase (TRAP)
- clinical features include splenomegaly (due to accumulation of hairy cells in red pulp) and “dry tap” on bone marrow aspiration (due to marrow fibrosis)
- lymphadenopathy is usually absent
- excellent response to 2-CDA (cladribine), an adenosine deaminase inhibitor; adenosine accumulates to toxic levels in neoplastic B cells
24
Q
Adult T-Cell Leukemia/Lymphoma (ATLL)
A
- neoplastic proliferation of mature CD4+ T cells
- associated with HTLV-1
- most commonly seen in Japan and the Caribbean
- clinical features include rash (skin infiltration), generalized lymphadenopathy with hepatosplenomegaly, and lytic (punched-out) bone lesions with hypercalcemia
25
Q
Mycosis Fungoides
A
- neoplastic proliferation of mature CD4+ T cells that infiltrate the skin, producing localized skin rash, plaques, and nodules
- aggregates of neoplastic cells in the epidermis are called Pautrier microabscesses
- cells can spread to involve the blood, producing Sezary syndrome
- characteristic lymphocytes with cerebriform nuclei (Sezary cells) are seen on blood smear
26
Q
Myoproliferative Disorders (MPD) Basic Principles
A
- neoplastic proliferation of mature cells of myeloid lineage; disease of late adulthood
- results in high WBC count with 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; and progression to marrow fibrosis or transformation to acute leukemia
27
Q
Chronic Myeloid Leukemia (CML)
A
- neoplastic proliferation of mature myeloid cells, especially granulocytes and their precursors; basophils are characteristically increased
- drived by t(9;22) (Philadelphia chromosome) which generates a BCR-ABL fusion protein with increased tyrosine kinase activity
- first-line treatment is imatinib (Gleevac), which blocks tyrosine kinase activity
- splenomegaly is common
- enlarging spleen suggests progression to accelerated phase of disease; transformation to acute leukemia usually follows shortly thereafter
- can transform to AML (2/3 of cases) or ALL (1/3 of cases) since mutation is in a pluripotent stem cell
28
Q
Distinguishing CML from Leukemoid reaction (reactive neutrophilic leukocytosis)
A
- negative leukocyte alkaline phosphatase (LAP) stain (granulocytes in a leukemoid reaction are LAP positive)
- increased basophils (absent with leukemoid reaction)
- t(9;22) (absent in leukemoid reaction)
29
Q
Polycythemia Vera (PV)
A
- neoplastic proliferation of mature myeloid cells, especially RBCs
- granulocytes and platelets are also increased
- associated with JAK2 kinase mutation
- clinical symptoms are mostly due to hyperviscosity of blood
- blurry vision
- increased risk of venous thrombosis (e.g. hepatic vein, portal vein, and dural sinus)
- flushed face due to congestion (plethora)
- itching, especially after bathing (due to histamine release from increased mast cells)
- treatment is phlebotomy; second-line therapy is hydroxyurea
- without treatment, death usually occurs within one year
- PV must be distinguished from reactive polycythemia
30
Q
Distinguishing Between PV and Reactive Polycythemia
A
- 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 production from renal cell carcinoma, EPO is high, and SaO2 is normal
31
Q
Essential Thrombocythemia (ET)
A
- neoplastic proliferation of mature myeloid cells, especially platelets
- RBCs and granulocytes are also increased
- associated with JAK2 kinase mutation
- symptoms are related to an increased risk of bleeding and/or thrombosis
- rarely progresses to marrow fibrosis or acute leukemia
- no significant risk for hyperuricemia or gout
32
Q
Myelofibrosis
A
- neoplastic proliferation of mature myeloid cells, especially megakaryocytes
- associated with JAK2 kinase mutation (50% of cases)
- megakaryocytes produce excess platelet-derived growth factor (PDGF) causing marrow fibrosis
- clinical features include splenomegaly due to extramedullary hematopoiesis; leukoerythroblastic smear (tear-drop RBCs, nucleated RBCs, and immature granulocytes); increased risk of infection, thrombosis, and bleeding
33
Q
Lymphadenopathy (LAD) Basic Principles
A
- 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 with chronic inflammation (chronic lymphadenitis), metastatic carcinoma, or lymphoma
- in inflammation, lymph node enlargement is due to hyperplasia of particular regions of lymph node
- follicular hyperplasia (B-cell region) is seen with rheumatoid arthritis and early stages of HIV infection, for example
- paracortex hyperplasia (T-cell region) is seen with viral infections (e.g. infectious mononucleosis)
- hyperplasia of sinus histiocytes is seen in lymph nodes that are draining a tissue with cancer
34
Q
Lymphoma Basic Principles
A
- 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 based on cell type (e.g. B versus T), cell size, pattern of cell growht, expression of surface markers, and cytogenetic translocations
- small B cells: follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma (i.e. CLL cells that involve tissue)
- intermediate-sized B cells: Burkitt lymphoma
- large B cells - diffuse large B-cell lymphoma
35
Q
Non-Hodgkin Lymphoma
A
- Overall Frequency: 60%
- Malignant Cells: lymphoid cells
- Composition of Mass: lymphoid cells
- Clinical: painless lymphadenopathy, usually arises in late adulthood
- Spread: diffuse; often extranodal
- Staging: limited importance
- Leukemic Phase: occurs
36
Q
Hodgkin Lymphoma
A
-Overall Frequency: 40%
-Malignant Cells: Reed-Sternberg cells
-Composition of Mass: predominantly reactive cells (inflammatory cells and fibrosis)
-Clinical: painless lymphadenopathy occasionally with “B” symptoms, usually arises in young adults
-Spread: contiguous; rarely extranodal
-Staging: guides therapy; radiation is the mainstay of treatment
Leukemic Phase: does not occur
37
Q
Follicular Lymphoma
A
- subtype of non-Hodgkin lymphoma
- neoplastic proliferation of small B cells (CD20+) that form follicle-like nodules
- presents in late adulthood with painless lymphadenopathy
- driven by t(14;18)
- BCL2 on chrom. 18 translocates to the Ig heavy chain locus on chrom. 14
- results in overexpression of Bcl2, which inhibits apoptosis
- treatment is reserved for patients who are symptomatic and involves low-dose chemotherapy or rituximab
- progression to diffuse large B-cell lymphoma is an important complication; presents as an enlarging lymph node
38
Q
Rituximab
A
-anti-CD20 antibody
39
Q
Distinguishing Follicular Lymphoma from Reactive Follicular Hyperplasia
A
- subtype of non-Hodgkin lymphoma
- follicular lymphoma has disruption of normal lymph node architecture (maintained in follicular hyperplasia)
- follicular lymphoma has lack of tingible body macrophages in germinal centers (tingible body macrophages are present in follicular hyperplasia)
- follicular lymphoma has Bcl2 expression in follicles (not expressed in follicular hyperplasia)
- follicular lymphoma has monoclonality (follicular hyperplasia is polyclonal)
40
Q
Mantle Cell Lymphoma
A
- subtype of non-Hodgkin lymphoma
- neoplastic proliferation of small B cells (CD20+) that expands the mantle zone
- presents in late adulthood with painless lymphadenopathy
- driven by t(11;14)
- cyclin D1 gene on chrom. 11 translocates to Ig heavy chain locus on chrom. 14
- overexpression of cyclin D1 promotes G1/S transition in the cell cycle, facilitating neoplastic proliferation
41
Q
Marginal Zone Lymphoma
A
- subtype of non-Hodgkin lymphoma
- neoplastic proliferation of small B cells (CD20+) that expands the marginal zone
- associated with chronic inflammatory states such as Hashimoto thyroiditis, Sjogren syndrome, and H pylori gastritis
- the marginal zone is formed by post-germinal center B cells
- MALToma is marginal zone lympoma in mucosal sites
- gastric MALToma may regress with treatment of H Pylori
42
Q
Burkitt Lymphoma
A
- subtype of non-Hodgkin lymphoma
- neoplastic proliferation of intermediate-sized B cells (CD20+)
- associated with EBV
- 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 translocations of c-myc (chrom. 8)
- t(8;14) is most common, resulting in translocation of c-myc to the Ig heavy chain locus on chrom. 14
- overexpression of c-myc oncogene promotes cell growth
- characterized by high mitotic index and “starry-sky” appearance on microscopy
43
Q
Diffuse Large B-Cell Lymphoma
A
- subtype of non-Hodgkin lymphoma (most common form)
- neoplastic proliferation of large B cells (CD20+) that grow diffusely in sheets
- clinically aggressive (high-grade)
- arises sporadically or from transformation of a low-grade lymphoma (e.g. follicular lymphoma)
- presents in late adulthood as an enlarging lymph node or an extranodal mass
44
Q
Hodgkin Lymphoma (HL) Basic Principles
A
- neoplastic proliferation of Reed-Sternberg (RS) cells, which are large B cells with multilobed nuclei and prominent nucleoli (“owl-eyed nuclei”)
- classically positive for CD15 and CD30
- RS cells secrete cytokines
- occasionally results in “B” symptoms
- 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
45
Q
“B” Symptoms
A
- fevers
- chills
- weight loss
- night sweats
46
Q
Nodular Sclerosis Hodgkin Lymphoma
A
- nodular sclerosis is the most common subtype 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)
47
Q
Subtypes of Hodgkin Lymphoma
A
- nodular sclerosis
- lymphocyte-rich
- mixed cellularity
- lymphocyte-depleted
48
Q
Lymphocyte-Rich HL
A
-has the best prognosis
49
Q
Mixed Cellularity HL
A
-is often associated with abundant eosinophils (RS cells produce IL-5)
50
Q
Lymphocyte-Depleted HL
A
- the most aggressive of all types
- usually seen in the elderly and HIV-positive individuals
51
Q
Multiple Myeloma
A
- 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 may be present; stimulates plasma cell growth and immunoglobulin production
52
Q
Clinical Features of Multiple Myeloma
A
- bone pain with 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
- elevated serum protein: neoplastic plasma cells produce immunoglobulin: M spike is present on serum protein electrophoresis (SPEP), most commonly due to monoclonal IgG or IgA
- increased risk of infection: monoclonal antibody lacks antigenic diversity; infection is the most common cause of death in multiple myeloma
- Rouleaux formation of RBCs on blood smear: increased serum protein decreases charge between RBCs
- primary AL amyloidosis: free light chains circulate in serum and deposit in tissues
- proteinuria: free light chain is excreted in the urine as Bence Jones protein; deposition in kidney tubules leads to risk for renal failure (myeloma kidney)
53
Q
Monoclonal Gammopathy of Undetermined Significance (MGUS)
A
-increased serum protein with M spike on SPEP; other features of multiple myeloma are absent (e.g. no lytic bone lesions, hypercalcemia, AL amyloid, or Bence Jones proteinuria)
54
Q
Waldenstrom Macroglobulinemia
A
- B-cell lymphoma with monoclonal IgM production
- generalized lymphadenopathy; lytic bone lesions are absent
- increased serum protein with M spike (comprised of IgM)
- visual and neurologic deficits (e.g. retinal hemorrhage or stroke) - IgM (large pentamer) causes serum hyperviscosity
- bleeding: viscous serum results in defective platelet aggregation
- acute complications are treated with plasmapheresis, which removes IgM from the serum
55
Q
Langerhans Cell Histiocytosis (Basic Principles)
A
- Langerhans cells are specialized dendritic cells found predominantly 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
56
Q
Letterer-Siwe Disease
A
- 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
57
Q
Eosinophilic Granuloma
A
- 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
58
Q
Hand-Schuller-Christian Disease
A
- malignant proliferation of Langerhans cells
- classic presentation is scalp rash, lytic skull defects, diabetes insipidus, and exophthalmos in a child
