WBC Disorders Flashcards
Basic principles of Leukopenia and Leukocytosis
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
Neutropenia
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
Lymphopenia
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
Causes of neutrophilic leukocytosis
- 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
Causes of monocytosis
- chronic inflammatory states (autoimmune or infectious)
- malignancy
Causes of eosinophila
- allergic reactions (type I hypersensitivity)
- parasitic infections
- Hodgkins lymphoma
eosinophila is driven by increased eosinophil chemotactic factor
Causes of basophila
Classically seen in CML
Causes of lymphocytic leukocytosis
- 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
Infectious Mononucleosis
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
Complications of mono
- 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
Basic principles of acute leukemia
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
Acute lymphoblastic leukemia (ALL)
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
B-ALL
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+)
T-ALL
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
Acute myeloid leukemia
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
Subtypes of AML
- 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 - Acute monocytic leukemia = proliferation of monoblasts, usually lack MPO
- blasts characteristically infiltrate gums - Acute megakaryoblastic leukemia = proliferation of megakaryoblasts –> lack MPO
- associated with Down syndrome (usually before the age of 5)
Myelodysplastic syndromes
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
Basic principles of chronic leukemia
Neoplastic proliferation of mature circulating lymphocytes –> characterized by a high WBC count
- usually insidious in onset and seen in older adults
Chronic lymphocytic leukemia
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
Hairy cell leukemia
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
Adult T cell leukemia/lymphoma
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
Mycosis fungoides
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
Basic principles of myeloproliferative disorders
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
Chronic myeloid leukemia
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
How to distinguish CML from a leukemoid reaction (reactive neutrophilic leukocytosis)
- 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
Polycythemia vera
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
How to distinguis PV from reactive polycythemia
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
Essential thrombocytopenia
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
Myelofibrosis
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
Lymphadenopathy
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
Basic principles of lymphoma
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
Follicular 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 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
How to distinguish follicular lymphoma from reactive follicular hyperplasia
- Disruption of normal lymph node architecture –> maintained in normal follicular hyperplasia
- Lack of tingible body macrophages in germinal centers –> present in follicular hyperplasia
- Bcl2 expression in follicles –> not expressed in follicular hyperplasia
- Monoclonality –> follicular hyperplasia is polyclonal
Mantle cell lymphoma
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
Marginal zone lymphoma
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
Burkitt 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 –> 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
Diffuse large B cell lymphoma
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
Hodgkin Lymphoma
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
Subtypes of Hodgkin lymphoma
- 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) - Lymphocyte rich –> has best prognosis
- Mixed cellularity –> often associated with abundant eosinophils (RS cells produce IL-5)
- Lymphocyte depleted –> most aggressive type, usually seen in the elderly and HIV positive people
Multiple myeloma
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
Clinical features of multiple myeloma
- 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 - Elevated serum protein –> neoplastic plasma cells produce immunoglobulin
- M spike is present on serum protein electrophoresis (SPEP) –> most commonly due to IgG or IgA - Increased risk of infection –> monoclonal antibody lacks antigenic diversity
- infection is the most common cause of death - Rouleaux formation of RBCs on blood smear –> increased serum protein decreases charge between RBCs and they aggregate
- 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)
Monoclonal gammopathy of undetermined significants (MGUS)
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
Waldenstrom macroglobulinemia
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
Langerhans cell histiocytosis
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
