Chapter 6: WBC Disorders COPY

Question 1

leukopenia

• neutropenia
• lymphopenia

Answer 1

NEUTROPENIA: decr number of circulating neutrophils

causes

• drug toxicity: damage to stem cells → decr production of WBC
• severe infection: incr movement of neutrophils into tissues → decr in circulating amt

tx: GM-CSF or F-CSF to boost granulocyte production

LYMPHOPENIA: decr number of circulating lymphocytes

causes

• immunodef
• high cortisol state: induced apop of lymphocytes
• autoimmune destruction
• whole body radiation

Question 2

leukocytosis

Answer 2

incr circulating neutrophils

causes:

• bacterial infection or tissue necrosis: induces release of marginated pool, bone marrow neutrophils (incl immature forms)
  
  • see a LEFT SHIFT: decreased Fc receptors (CD 16)
• monocytosis: incr circulating monocytes due to chronic infl state and/or malignancy
• eosinophillia: incr circulating eosinophils due to allergic rxn, parasitic infection, HL
• basophilia: incr circulating basophils (classic: CML)
• lymphocytic leukocytosis: incr circulating lymphocytes (viral infection, Bordetella pertussis inf)

Question 3

infectious mononucleosis

[p54 - didn’t type it all out, this card is just here as placeholder for that section]

Question 4

ACUTE LEUKEMIA

ALL

Answer 4

acute lymphoblastic leukemia

• neoplastic accumulation of lymphoblasts (>20%) in bone marrow
  
  • positive nuclear staining for TdT (DNA polymerase), which is seen in lymphoblasts (but not myeloid blasts or mature lymphocytes)
• most commonly in KIDS
  
  • assoc with Down syndrome over age 5
• two subtypes:
  
  1. B-ALL (most common)
     
     • CD10, CD19, CD20
     • good response to response to chemo
     • t 12;21 more in kids, good prognosis
     • t 9;22 more in adults, poor prognosis
  2. T-ALL
     
     • CD2-CD8, but no CD10
     • teenagers presenting with thymic/mediastinal mass

Question 5

ACUTE LEUKEMIA

AML

Answer 5

neoplastic accumulation of MYELOBLASTS

• Neoplastic accumulation of immature myeloid cells (>20%) in the bone marrow
• MPO+ (positive cytoplasmic staining for myeloperoxidase) → crystal aggregates visible as Auer rods
• commonly in older adults
• key subtypes:
  
  1. APL
  2. acute monocytic leukemia
  3. acute megakaryoplastic leukemia
• may arise from pre-existing dysplasia, esp with prior exposure to alkylating agents or radiotx
  
  • Myelodysplastic syndromes present with cytopenias, hypercellular bone marrow, abnormal maturation of cells, incr blasts (<20%)
  • most pt die from infection or bleeding, some progress to acute leukemia

Question 6

ACUTE LEUKEMIA

Acute Promyelocytic Leukemia: APL

Answer 6

acute promyelocytic leukemia

• t (15;17) - translocation of RAR (chr17) to chr15
• RAR disruption blocks maturation → promyelocytles accumulate
  
  • abnormal promyelocytes contain primary granules → incr risk for DIC
• tx: ATRA (all trans retinoic acid) : binds altered receptor, causing blasts to mature and die

Question 7

ACUTE LEUKEMIA

AML

acute monocytic leukemia

Answer 7

• proliferation fo monoblasts (usually lack MPO)
• characteristically infiltrate GUMS

Question 8

ACUTE LEUKEMIA

AML

acute megataryoblastic leukemia

Answer 8

• proliferation fo megakaryoblasts (lack MPO)
• assoc with Downs syndrome before age 5

Question 9

CHRONIC LEUKEMIA

basics

Answer 9

• neoplastic prolif of MATURE circulating lymphocytes
• characterized by high WBC count
• insidious in onset
• seen in older adults

Question 10

chronic lymphocytic leukemia (CLL)

Answer 10

​CHRONIC LEUKEMIA

• neoplastic prolif of naive B cells (coexpress CD5, CD20)
• increased lymphocytes and smudge cells on blood smear
• involvement of lymph nodes → generalized lymphadenopathy
  
  • aka “small lymphocytic leukemia”
• complications:
  
  • hypogammaglobulinemia (bc neoplastic B cells dont produce Ig like normal B cells would)
  • autoimmune hemolytic anemia
  • transformation to diffuse large B cell lymphoma (Richter transformation)
    
    • marked by enlarging lymph node, spleen

most common leukemia overall

Question 11

hairy cell leukemia

Answer 11

CHRONIC LEUKEMIA

• neoplastic proliferation of mature B cells characterized by hairy cytoplasmic processes
• cells positive for TRAP (tartrate resistant acid phosphatase)
• clinical features:
  
  • splenomegaly (due to accum of hairy cells in red pulp)
  • “dry tap” on bone marrow aspiration (due to marrow fibrosis)
  • LYMPHADENOPATHY ABSENT!
• excellent response to cladribine/2CDA (adenosine deaminase inhibitor) → causes adenosine to accumulate to toxic levels in neoplastic B cells

Question 12

adult T cell leukemia

Answer 12

CHRONIC LEUKEMIA

• neoplastic proliferation of mature CD4 T cells
• associated with HTLV1
  
  • commonly seen in Japan, Caribbean
• clinical features
  
  • rash (skin infiltration)
  • generalized lymphadenopathy with hepatosplenomegaly
  • lytic bone lesions with hypercalcemia
    
    • consider this as ddx to multiple myeloma, esp if see skin rashes too!

Question 13

mycosis fungoides

Answer 13

CHRONIC LEUKEMIA

• neoplastic proliferation of mature CD4 T cells
• infiltrate skin, producing localized rash, plaques, nodules
  
  • aggregates of neoplastic cells in epidermis: Pautrier microabscesses
• ​cells can spread to involve blood → Sezary syndrome
  
  • ​characteristic lymphocytes with cerebriform nuclei (Sezary cells) on smear

Question 14

MYELOPROLIFERATIVE DISORDERS

basics

Answer 14

• neoplastic proliferation of mature cells of myeloid lineage
• avg age: 50-60
• see high WBC count, hypercellular bone marrow
  
  • cells of all myeloid lineages increased
  • classify based on dominant myeloid cell produced
• complications
  
  • incr risk for hperuricemia and gout (high turnover of cells/nuclei)
  • progression to marrow fibrosis or transformation to acute leukemia

Question 15

chronic myeloid leukemia

Answer 15

MPD

• neoplastic prolif of mature myeloid cells, esp GRANULOCYTES AND PRECURSORS (basophils characteristically increased
• t (9;22) → Philadelphia chromosome = BCR-ABL fusion protein with increased tyr kinase activity
  
  • ​tx: imatinib (blocks BCR-ABL tyr kinase activity)
• splenomegaly common
  
  • spleen enlarging? suggests progression to accelerated phase of disease, followed rapidly by transformation to acute leukemia
  • transformation to…
    
    • AML (2/3 cases)
    • ALL (1/3 cases)

how can you differentiate CML from a leukemoid rxn?

CML will show…

• negative for LAP (leukocyte alkaline phosphatase, which will be present in granulocytes in a leukemoid rxn)
• incr basophils
• t(9;22)

Question 16

polycythemia vera

Answer 16

MPD

• neoplastic proliferation of mature myeloid cells, esp RBCS (granulocytes and platelets also incr)
• associated with JAK2 kinase muatations
• clinical symptoms (mostly due to hyperviscosity of blood)
  
  • blurry vision, headache
  • flushed face/congestion (plethora)
  • incr risk of venous thrombosis
  • itching/pruritis after bathing (bc of extra mast cells releasing histamine)
• treatment:
  
  • 1st line: phlebotomy
  • 2nd line: hydroxyurea
  • w/out tx, death within a year

how do you distinguish PV from reactive polycythemia?

look at SaO2 and levels of epo

• PV: low epo, normal SaO2
• reactive polycythemia (high alt/lung disease): high epo, low SaO2
• reactive polycythemia (ectopic epo production): high epo, normal SaO2

Question 17

essential thrombocythemia

Answer 17

MPD

• neoplastic proliferation of mature myeloid cells, esp platelets (RBCs, granulocytes also incr)
• assoc with JAK2 kinase mutation
• symptoms realted to incr risk of bleeding and/or thrombosis
  
  • rarely progresses to marrow fibrosis or acute leukemia
  • no significant risk for hyperuricemia or gout

Question 18

myelofibrosis

Answer 18

MPD

• neoplastic prolif of mature myeloid cells, esp megakaryocytes
• assoc with JAK2 kinase mutation (50%)
• megakaryocytes produce excess PDGF → causes marrow fibrosis
• clinical features
  
  • splenomegaly due to extramedullary hematopoiesis
  • leukoerythroblastic smear (tear drop RBC, nucleated RBC, immature granulocytes)
  • incr risk of infection, thrombosis, bleeding

Question 19

LYMPHADENOPATHY

basics

Answer 19

enlarged lymph nodes

• painful? lymph nodes draining region of acute infection
• panless? chronic infl, metastatic carcinoma, lymphoma
  
  • inflammationL LAD due to hyperplasia of particular regions of lymph node

regions of lymph node:

1. follicular hyperplasia (B cell region): ex. rheumatoid arthritis, early HIV
2. paracortex hyperplasia (T cell region): ex. viral inf
3. hyperplasia of sinus histiocytes: lymph nodes draining a tissue with cancer

Question 20

LYMPHOMA

basics

Answer 20

• neoplastic proliferation of lymphoid cells that forms a mass
• can arise in lymph node or extranodal tissue
• two types
  
  • nonHodgkin lymphoma
    
    • classified based on B vs T, cell size, pattern of growth, expression of surface markers, cytogenetic translocations
    1. small B cells (follicular, mantle cell, marginal zone, small lymphocytic lymphoma)
    2. intermediate size B cells (Burkitt lymphoma)
    3. large B cells (diffuse large B cell lymphoma)
  • Hodgkin lymphoma
    
    • subtypes
    1. nodular sclerosis
    2. mixed cellularity
    3. lymphocyte rich
    4. lymphocyte depleted

Question 21

follicular lymphoma

Answer 21

NHL: small B cell (CD20)

• neoplastic prolif of small B cells that form follicle like nodules
• late adulthood w/ painless LAD
• t(14;18) → BCL2 to IgH locus on chr14
  
  • overexpression of Bcl2 (anti-apoptotic)
  • ​​tx: low dose chemo or rituximab (only for symtomatic pts)
• complicaation: progression to diffuse large B cell lymphoma: presents as enlarging lymph node

how do you tell the different between follicular lymphoma and reactive follicular hyperplasia?

follicular lymphoma shows…

• disruption of lymph node architecture
• lack of tingible body macrophages in germinal centers (which would be present in regular hyperplasia)
• Bcl2 expression
• monoclonality

Question 22

mantle cell lymphoma

Answer 22

NHL: small B cells (CD20)

• neoplastic proliferation of small B cells expanding into mantle zone
• late adulthood w/ painless LAD
• t(11;14) → cyclin D1 to IgH locus on chr14
  
  • ​overexpression of cyclin D1 promotes G1/S transition → neoplastic prolif

Question 23

marginal zone lymphoma

Answer 23

NHL: small B cell (CD20): post-germinal center B cells

• neoplastic proliferation of small B cells expanding into marginal zone
• assoc with chronic infl states (Hashimoto thyroiditis, Sjogren syndrome, H pylori gastritis)
• MALToma: marginal zone lymphoma formed in mucosal sites
  
  • miiiight regress with treatment of H pylori

Question 24

Burkitt lymphoma

Answer 24

NHL: intermediate B cells (CD20)

• neoplastic proliferation of intermediate sized B cells
• assoc with EBV
• classic presentation: extranodal mass in child or young adult
  
  • African form: JAW
  • sporadic form: ABDOMEN
• translocations of c-myc → overexpression of c-myc oncogene promotes cell growth
  
  • ​t(8;14) most common
• ​high mitotic index, “starry sky” appearance

Question 25

diffuse large B cell lymphoma

Answer 25

NHL: large B cell (CD20) * neoplastic proliferation of large B cells growing diffusely in sheets * most common form of NHL * clinically aggressive (high grade) * arises sporadically or from transformation of a low grade lymphoma (ex. follicular lymphoma) * presents in late adulthood as enlarging lymph node or extranodal mass

Question 26

Hodgkin lymphoma basics 4 subtypes

Answer 26

* neoplastic proliferation of **Reed Sternberg cells** (large B with multilobed nuclei, prominent nucleoli, CD15, CD30) * secrete cytokines * sometimes see B symptoms (fever, chills, wt loss, night sweats) * attract reactive lymphocytes, plasma cells, macrophages, eosinophils * can lead to fibrosis * reactive inflammatory cells make up bulk of tumor - used as basis for classification 1. nodular sclerosis * most common subtype (70%) * classic presentation: young adult female with enlarging cervical/mediastinal lymph node * lymph node divided by bands of sclerosis * RS cells present as lacunar cells 2. mixed cellularity * assoc with abundant eosinophils (RS cells make IL5) 3. lymphocyte rich * best prognosis 4. lymphocyte depleted * most aggressive, usually in elderly and/or HIV+

Question 27

multiple myeloma

Answer 27

plasma cell disorder * malignant proliferation of **plasma cells** in bone marrow * most common primary malignancy of bone * **high serum IL6** can be present → stimulates plasma cell growth and Ig production * have increased number of large plasma cells that are abnormal * plasma cells have nucleus on edge of cell * can be binucleated * clinical features * bone pain with hypercalcemia: **lytic, punched out skeletal lesions, esp vertebrae/skull** * **​**neoplastic plasma cells activate RANK receptor on osteoclasts → bone destruction * **elevated serum protein: M spike on SPEP** * **​**most common due to IgG, IgA * increased risk of infection * Rouleaux formation (incr serum protein → decr charge between RBCs) * primary AL amyloidosis: free light chains circulate in serum, deposit in tissues * proteinuria: free light chain excreted as Bence Jones protein → risk for renal failure (myeloma kidney)

Question 28

monoclonal gammopathy of undetermined significance (MGUS)

Answer 28

* increased serum protein with M spike on SPEP **but no other features of multiple myeloma** * common in elderly * 1% of MGUS patients progress to multiple myeloma each year

Question 29

Waldenstrom macroglobulinemia

Answer 29

* B cell lymphoma with monoclonal **IgM** production * clinical features * generalized LAD * NO LYTIC BONE LESIONS * incr serum protein with M spike (IgM) * visual, neuro deficits (ex. retinal hemorrhage/stroke) bc IgM causes hyperviscosity * bleeding: viscosity → defective platelet aggregation * complications treated with plasmapheresis to remove IgG from serum

Question 30

Langerhans cell histiocytosis

Answer 30

Langerhans cells: specialized dendritic cells found predominantly in skin * derived from bone marrow monocytes * present antigen to naive T cells **neoplastic proliferation of Langerhans cells** * **characteristic Birbeck granules (tennis racket)** * **cells CD1a+ and S100+ on immunohistochem**

Question 31

Letterer-Siwe disease

Answer 31

Langerhans cell histiocytosis * malignant prolif of Langerhans cells * classic presentation: under 2 yrs * skin rash * cystic skeletal defects * multiple organs can be involved, rapidly fatal

Question 32

eosinophilic granuloma

Answer 32

Langerhans cells histiocytosis * benign proliferation of Langerhans cells in bone * classic presentation: pathologic fracture in adolescent * skin not involved * biopsy: Langerhans cells with mixed infl cells (numerous eosinophils)

Question 33

Hand-Schuller-Christian disease

Answer 33

Langerhans cells histiocytosis * malignant proliferation of Langerhans cells * classic presentation: child * scalp rash * lytic skull defects * diabetes insipidus * exophthalmos