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Pathoma > WBC Disorders > Flashcards

WBC Disorders Flashcards

1
Q

Basic principles of Leukopenia and Leukocytosis

A

Hematopoeisis occurs via a step wise maturation of CD34+ hematopoietic stem cells

Cells mature and are released from the bone marrow into the blood

A normal WBC count is approx 5-10 K/microL

  • a low WBC count = leukopenia
  • a high WBC count = leukocytosis
  • a low or high WBC count is usually due to a decrease or increase in one particular cell lineage
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2
Q

Neutropenia

A

Neutropenia refers to a decreased number of circulating neutrophils

Causes

  • drug toxicity (eg chemo with alkylating agents) –> damage to stem cells results in decreased production of WBCs, especially neutrophils
  • severe infection (eg gram neg sepsis) –> 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
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3
Q

Lymphopenia

A

Decreased number of circulating lymphocytes

Causes

  • Immunodeficiency (eg DiGeorge syndrome or HIV)
  • high cortisol state –> induces apoptosis of lymphocytes
  • autoimmune destruction (eg SLE)
  • whole body radiation –> lymphocytes are highly sensitive to radiation –> lymphopenia is the earliest change to emerge after whole body radiation
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4
Q

Causes of neutrophilic leukocytosis

A
  • 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 = release of marginated pool of neutrophils
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5
Q

Causes of monocytosis

A
  • chronic inflammatory states (autoimmune or infectious)

- malignancy

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6
Q

Causes of eosinophila

A
  • allergic reactions (type I hypersensitivity)
  • parasitic infections
  • Hodgkins lymphoma

eosinophila is driven by increased eosinophil chemotactic factor

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7
Q

Causes of basophila

A

Classically seen in CML

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8
Q

Causes of lymphocytic leukocytosis

A
  • viral infections –> T lymphocytes undergo hyperplasia in response to virally infected cells
  • bordetella pertussis infection –> bacteria produce lymphocytosis promoting factor –> blocks circulating lymphocytes from leaving the blood to enter the lymph node
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9
Q

Infectious Mononucleosis

A

EBV infection that results in a lymphocytic leukocytosis comprised of reactive CD8 T cells
- CMV is a less common cause

EBV primarily infects:

  • oropharynx –> results in pharyngitis
  • liver –> results 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 node paracortex
  • splenomegaly due to T-cell hyperplasia in the periarterial lymphatic sheath
  • high WBC count with atypical lymphocytes (reactive CD8 T cells) in the blood

Monospot test is used for screening

  • detects IgM antibodies that cross-react with horse or sheep RBCs = heterophile antibodies
  • usually turns positive within 1 week after infection
  • a neg monospot test suggests CMV as a possible cause of mono
  • definitive diagnosis is made by serologic testing for the EBV viral capsin antigen
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10
Q

Complications of mono

A
  • increased risk for splenic rupture –> patients are advised to avoid contact sports for one 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 develops
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11
Q

Basic principles of acute leukemia

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 –> results in a high WBC
- blasts are large, immature cells, often with punched out nucleoli

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12
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 after the age of 5)

Subclassified into B-ALL and T-ALL based on surface markers

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13
Q

B-ALL

A

Most common type of ALL

  • usually characterized by lymphoblasts (TdT+) that express CD10, CD19 and CD20
  • excellent response to chemo –> requires prophylaxis to scrotum and CSF

Prognosis is based on cytogenetic abnormalities

  • t(12;21) –> good prognosis, more commonly seen in children
  • t(9;22) –> poor prognosis, more commonly seen in adults (Ph+)
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14
Q

T-ALL

A

Characterized by lymphoblasts (TdT+) that express markers ranging from CD2-CD8
- blasts do not express CD10

Usually presents in teenagers as a mediastinal (thymic) mass –> called acute lymphoblastic lymphoma because the malignant cells for a mass

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15
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
  • crystal aggregates of MPO may be seen as Auer rods

Most commonly arises in older adults (50-60 yrs)

Subclassified based on cytogenetic abnormalities, lineage of myeloblasts, and surface markers

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16
Q

Subtypes of AML

A
  1. Acute promyelocytic leukemia = characterized by t(15;17) –> involves translocation of the RAR on chromosome 17 to chromosome 15
    - RAR disruption blocks maturation and promyelocytes accumulate
    - abnormal promyelocytes contain numerous primary granules that increase the risk for DIC
    - treatment is with all-trans-retinoic acid (ATRA) –> binds the altered receptor and causes the blasts to mature
  2. Acute monocytic leukemia = proliferation of monoblasts, usually lack MPO
    - blasts characteristically infiltrate gums
  3. Acute megakaryoblastic leukemia = proliferation of megakaryoblasts –> lack MPO
    - associated with Down syndrome (usually before the age of 5)
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17
Q

Myelodysplastic syndromes

A

May give rise to AML, 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
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18
Q

Basic principles of chronic leukemia

A

Neoplastic proliferation of mature circulating lymphocytes –> characterized by a high WBC count
- usually insidious in onset and seen in older adults

19
Q

Chronic lymphocytic leukemia

A

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 –> called small lymphocytic lymphoma

Complications

  • hypogammaglobulinemia –> infection is the most common cause of death
  • autoimmune hemolytic anemia
  • transformation to diffuse large B cell lymphoma –> marked clinically by an enlarging lymph node of spleen
20
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 the red pulp) and “dry tap” on bone marrow aspiration (due to marrow fibrosis)
  • lymphadenopathy is usually absent

Excellent response to cladribine = adenosine deaminase inhibitor –> adenosine accumulates to toxic levels in neoplastic B cells

21
Q

Adult T cell leukemia/lymphoma

A

Neoplastic proliferation of mature CD4 T cells

  • associated with HTLV-1
  • most commonly seen in Japan and the caribbean

Clinical features

  • rash (skin infiltration)
  • generalized lymphadenopathy with hepatosplenomegaly
  • lytic bone lesions with hypercalcemia
22
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 = pautrier microabscesses

Cells can spread to involve the blood –> called Sezary syndrome
- characteristic lymphocytes with cerebriform nuclei are seen on blood smears

23
Q

Basic principles of myeloproliferative disorders

A

Neoplastic proliferation of mature cells of myeloid lineage

  • disease of late adulthood (avg age 50-60 years)
  • 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

  • increased risk for hyperuricemia and gout due to high turnover of cells
  • progression to marrow fibrosis or transformation to acute leukemia
24
Q

Chronic myeloid leukemia

A

Neoplastic proliferation of mature myeloid cells, especially granulocytes and their precursors
- basophils are characteristically increased

Driven by t(9;22) = philadelphia chromosome –> generates a BCR-ABL fusion protein with increased TK activity
- first line treatment is imatinib –> blocks TK 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 cells

25
Q

How to distinguish CML from a leukemoid reaction (reactive neutrophilic leukocytosis)

A
  1. Negative leukocyte alkaline phosphatase (LAP) stain –> granulocytes in a leukemoid reaction are LAP positive
  2. Increased basophils –> absent with leukemoid reaction
  3. t(9;22) –> absent in leukemoid reaction
26
Q

Polycythemia vera

A

Neoplastic proliferation of mature myeloid cells, especially RBCs –> granulocytes and platelets are also increased
- associated with JAK2 mutation

Clinical symptoms mainly due to hyperviscosity of blood

  • blurry vision and headache
  • increased risk of venous thrombosis (hepatic vein, portal vein, and dural sinus)
  • flushed face due to congestion
  • itching, especially after bathing (due to histamine release from increased mast cells)

Treatment –> phlebotomy, hydroxyrea
- without tx, death usually occurs within 1 year

27
Q

How to distinguis PV from reactive polycythemia

A

n 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
28
Q

Essential thrombocytopenia

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
29
Q

Myelofibrosis

A

Neoplastic proliferation of mature myeloid cells, especially megakaryocytes

  • associated with JAK2 kinase mutation
  • megakaryocytes produce excess PDGF –> causes marrow fibrosis

Clinical features

  • splenomegaly due to extramedullary hematopoiesis
  • leukoerythroblastic smear = tear drop RBCs, nucleated RBCs, and immature granulocytes
  • increased risk of infection, thrombosis and bleeding
30
Q

Lymphadenopathy

A

LAD refers to enlarged lymph nodes

  • painful LAD is usually seen in lymph nodes that are draining a region of acute infections = 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 the lymph node

  • follicular hyperplasia (B-cell region) –> seen with rheumatoid arthritis and early stages of HIV, for example
  • paracortex hyperplasia –> seen with viral infections
  • hyperplasia of sinus histiocytes –> seen with lymph nodes that are draining a tissue with cnacer
31
Q

Basic principles of lymphoma

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 and Hodgkin lymphoma

NHL is further classified based on cell type (B vs. T), cell size, patterns 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 (CLL that involves tissue)
  • intermediate sized B cells = Burkitt lymphoma
  • large B cells = diffuse large B cell lymphoma
32
Q

Follicular lymphoma

A

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 chromsome 18 translocates to the Ig heavy chain locus on chromosome 14
  • results in overexpression of Bcl2 = inhibits apoptosis

Treatment is reserved for patients who are symptomatic –> involves low dose chemo or rituximab

Progression to diffuse large B cell lymphoma is an important complication –> presents as an enlarging lymph node

33
Q

How to distinguish follicular lymphoma from reactive follicular hyperplasia

A
  1. Disruption of normal lymph node architecture –> maintained in normal follicular hyperplasia
  2. Lack of tingible body macrophages in germinal centers –> present in follicular hyperplasia
  3. Bcl2 expression in follicles –> not expressed in follicular hyperplasia
  4. Monoclonality –> follicular hyperplasia is polyclonal
34
Q

Mantle cell lymphoma

A

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

  • presents in late adulthood with painless lymphadenopathy
  • drived by t(11;14) –> cyclin D1 gene on chromosome 11 translocates to Ig heavy chain locus on chromosome 14
  • over expression of cyclin D1 promotes G1/S transition in the cell cycle, facilitating neoplastic proliferation
35
Q

Marginal zone lymphoma

A

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

  • associated with chronic inflammatory states such as hashimotos, sjogren syndrome, and h. pylori gastritis
  • the marginal zone is formed by post-germical center B cells
  • MALToma is marginal zone lymphoma in mucosal sites
  • gastric MALToma may regress with treatment of H. pylori
36
Q

Burkitt lymphoma

A

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 –> results in translocation of c-myc to the Ig heavy chain
  • overexpression of c-myc oncogene promotes cell growht = transcription activator

Characterized by high mitotic index + starry sky appearance on microscopy

37
Q

Diffuse large B cell lymphoma

A

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 transformation of a low grade lymphoma (eg follicular lymphoma)
- presents in late adulthood as an enlarging lymph node or an extranodal mass

38
Q

Hodgkin Lymphoma

A

Neoplastic proliferation of Reed-Sternberg cells = large B cells with multi-lobed nuclei and prominent nucleoli (owl eyed nuclei) –> classically positive for CD15 and CD30

RS cells secrete cytokines

  • occasionally results in B symptoms –> fever, chills, weight loss, and night sweats
  • attracts 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

39
Q

Subtypes of Hodgkin lymphoma

A
  1. Nodular sclerosing = most common subtype –> 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)
  2. Lymphocyte rich –> has best prognosis
  3. Mixed cellularity –> often associated with abundant eosinophils (RS cells produce IL-5)
  4. Lymphocyte depleted –> most aggressive type, usually seen in the elderly and HIV positive people
40
Q

Multiple myeloma

A

Malignant proliferation of plasma cells in the bone marrow

  • most common primary malignancy of bone –> metastatic cancer is the most common malignant lesion of bone overal
  • high serum IL-6 may be present –> stimulates plasma cell growth and immunoglobulin production
41
Q

Clinical features of multiple myeloma

A
  1. Bone pain with hypercalcemia –> neoplastic cells activate the RANK receptor on osteoclasts, leading to bone destruction
    - lytic, pumched out skeletal lesions are seex on x ray, especially in the vertebrae and skull
    - increased risk for fracture
  2. Elevated serum protein –> neoplastic plasma cells produce immunoglobulin
    - M spike is present on serum protein electrophoresis (SPEP) –> most commonly due to IgG or IgA
  3. Increased risk of infection –> monoclonal antibody lacks antigenic diversity
    - infection is the most common cause of death
  4. Rouleaux formation of RBCs on blood smear –> increased serum protein decreases charge between RBCs and they aggregate
  5. Primary AL amyloidosis –> free light chains circulate in serum and deposit in tissues
  6. 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)
42
Q

Monoclonal gammopathy of undetermined significants (MGUS)

A

Increased serum protein with M spike on SPEP –> other features of multiple myeloma are absent (no lytic bone lesions, hypercalcemia, AL amyloid, or bence jones proteinuria)
- common in elderly (seen in 5% of 70 year old people) –> 1% of patients with MGUS develop multiple myeloma each year

43
Q

Waldenstrom macroglobulinemia

A

B cell lymphoma with monoclonal IgM production

Clinical features

  • 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 –> removes IgM from the serum

44
Q

Langerhans cell histiocytosis

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 granules (tennis racket) are seen on electron microscopy
  • cells are CD1a and S1)) positive by immunohistochemistry

Pathoma (16 decks)

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