Unit 2: HEME ONC Flashcards
Types of simple leukocytosis
Monocytosis
Eosinophilia
Basophilia
Lymphocytic leukocytosis
What causes monocytosis
chronic inflammatory states (autoimmune and infections), and malignancy
What causes eosinophilia
Allergic rnxs (type 2)
parasites
Hodgins lymphoma
What mainly causes basophilia?
Chronic myeloid leukemia
What causes lymphocytic leukocytosis
Viral infections- T cells undergo hyperplasia
Bordetella pertussis infections- secretes toxin that stops lymphocytes entering lymph nodes
Infectious Mononucleosis simple explanation
Infections from either EBV or CMV
Causes increase of CD8
Elevated CD8 in IM leads to…
Generalized LAD (paracortex hyperplasia)
Splenomegaly (PALS hyperplasia)
High WBC with atypical lymphocytes (weirdly shaped cytoplasm)
What kind of test is used for EBV/IM
Monospot test
Explain monospot test
Serum IgM is used to see if it cross-reacts with sheep or horse red blood cells
EBV primary infects…
Oropharynx, causes pharyngitis
Liver, hepatitis
B cells
What are the types of acute leukemias?
Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
increased BLASTS
AML simple explanation
Inc of myeloid blasts that (some) are positive for MPO
most commonly seen in older adults
Auer rods in cytoplasm
what are the sub types of AML?
Acute promyelocytic leukemia
Acute monocytic leukemia
Acute megakaryoblastic leukemia
Explain Acute promyelocytic leukemia
inc promyelocytic blasts
t(15;17) of RAR on chromosome 17 to 15.
RAR disruptions maturation and promyeloblasts accumulate
These blasts contains granules that can lead to DIC
Treatment is ATRA
Explain acute monocytic leukemia
inc in monocytic blasts, lack MPO
blasts infiltrate gums
Explain acute megakaryoblastic anemia
inc in megakayro. , lack MPO
associated with downs, BEFORE age of 5
ALL simple explanation
inc of lymphoblasts, TdT positive
more common in children with Downs, AFTER age of 5
either B-ALL or T-ALL
Explain B-ALL
inc B cells (>20% in marrow)
most common type of ALL
positive for TdT, CD 10,19,20
great response to chemo
prognosis based on cytogenetic factors
-t12,21: good, seen in children
-t9,22: worse, seen in adults (Philidelphia ALL)
Explain T-ALL
inc T cells (>20% in marrow)
positive for TdT and CD2-8
Usually presents in Teenagers as a Thymic mass (acute lymphoblastic lymphoma)
Simple explanation of Chronic leukemia
Neoplastic prolifer. of MATURE LYMPHOCYTES (B and T cells) or MYELOID cells
usually seen in older adults
What are the types of chronic leukemia?
Chronic Lymphocytic Leukemia
Hairy Cell Leukemia
Adult T-Cell Leukemia/Lymphoma
Mycosis Fungoides
Which types of chronic leukemia involve B cells
CLL
Hairy cell leukemia
Which types of chronic leukemia involve T cells
Adult T-Cell Leukemia/Lymphoma
Mycosis Fungoides
Explain Chronic Lymphocytic leukemia
Neoplastic prolifer. of NAIVE B cells that co express CD5, 20
Most common Chronic leukemia
Inc lymphocytes and smudge cells on blood smear
Involvement of lymph nodes leads to generalized LAD called small lymphocytic lymphoma
What are the complications associated with CLL
Hypogammaglobulinemia- low Ig due to naive B cells never making any. Infection most common cause of death in these pts
Autoimmune hemolytic anemia- naive cells make self antibodies that stick to RBCs
Transformation to diffuse large B cell lymphoma (richter transformation)
Explain Hairy cell leukemia
Neoplastic prolif. of MATURE B cells with “hairy” cytoplasmic appearance
TRAP enzyme positive
What are the clinical features of hairy cell leukemia
Splenomegaly- due to hairy cells building up in red pulp
“dry tap” on bone marrow due to fibrosis
NO LAD
What drug does Hairy cell leukemia response well to
2-CDA (cladribine)- ADA inhibitor, inc adenosine which is toxic
Explain ATLL
Neoplastic prolife. of mature CD4 T cells
Associated with HTVL-1
What demographic is associated with HTVL-1
japanese and carribean
What are the clinical features of ATLL
Rash (skin infiltration)
Gen. LAD
Hepatosplenomeg.
Lytic bone lesions with hypercalcemia (Punched out lesions)
Explain Mycosis fungoides
Neoplastic prolifer. of mature CD4 t cells
T cells infiltrate the skin causing rash, nodules, amd plaques
What is seen on blood smear of a pt with mycosis fungoides
Sezary syndrome- lymphocytes with brain like nuclei (sezary cells)
what are the basic principles of Myeloproliferative disorders
Neoplastic prolifer. of MATURE cells of myeloid lineage. Late adulthood disease
All myeloid cells inc with hypercellular bone marrow
Inc risk of hyperuricemia and gout due to inc cell turnover
Progression to marrow fibrosis or transformation to acute leukemia
What are the types of MPD
Chronic myeloid leukemia
Polycythemia Vera
Essential thrombocytopenia
Myelofibrosis
Explain simply what is CML
Inc neoprolifer. of myeloid cells, especially granulocytes
-Basophilia seen in this disease
Due to t9:22 (philly chromosome), which generates BCR-ABL fusion protein with inc. tyrosine kinase activity
Splenomegaly common which signifies progression to either AML or ALL
What is the translocation in CML
t9:22
Philly chromosome
BCR-ABL
How is CML distinguished from a leukemoid reaction?
- Neg leukocyte alkaline phosphate (LAP) stain
- Inc Basophils
- t9:22
Simple explanation of Polycythemia vera
Neoplastic proliferation of mature myeloid cells, esp. RBCs
Associated with JAK2 Kinase mutation
treatment: phlebotomy; then hydroxyurea
-without treatment=death
What are the clinical symptoms of PV
Hyperviscosity of blood which cases,
-Blurry vision and headache
-Inc risk of venous thrombosis (hepatic, portal veins)
- Flushed face due to congestion
-Itching, esp after bathing
How is PV distinguished from reactive polycythemia
-In PV, EPO decre., SaO2 normal
-In reactive poly. due to lung disease or high altitude, SaO2 is low, EPO inc
-Renal cell carcinoma can cause reactive poly. due to high EPO, SaO2 normal
Simple explanation of Myelofibrosis
Neoplastic prolifer. of mature myeloid cells, esp. megakaryo
Associated with JAK2 kinase mutation
Megakaryocytes produce excess platelet derived growth factor, leading to marrow fibrosis
What are the clinical features of Myelofibrosis
Splenomeg. due to extramedullary hematopoiesis
Leukoerythroblastic smear (tear drop RBCs, nucleated RBCs, immature granulocytes
Inc risk of infections, thrombosis, bleeding
Simple explanation of Essential thrombocythemia
Neoplastic prolifer. of mature myeloid cells, esp. platelets
Associated with JAK2 kinase mutation
Clinical symptoms of essential thrombocythemia
Increased risk for bleeding and/ or thrombosis
-rarely progresses to acute leukemia or marrow fibrosis
- no risk for hyperuricemia or gout
Main basic principles of lymphoma
Lymph tissue mass
causes be either B cell or T cell neoplasm
Characterized by cell size, location of mass, surface markers, B vs T cells
Follicular Lymphoma simple explanation
Neoplasmic prolifer or small B cells in follicles
Presents in late adulthood, w/ painless LAD
Driven by t14;18
-BCL2 translocation to chrom. 14
- inc BCL2 inhibits apoptosis
What is the treatment for follicular lymphoma
Low dose chem or rituximab
Only if patient is symptomatic
What can follicular lymphoma progress to?
Diffuse large cell lymphoma
How is follicular lymphoma distinguished from reactive follicular hyperplasia
- Disruption of normal lymph node architecture
- Lack of tingible macrophages in germinal centers
- Bcl2 expression in follicles
- Monoclonality (poly. in reactive hyperplasia
Simple explanation of mantle cell lymphoma
neoplastic prolif. of small B cells in the mantle zone
Presents in late adulthood with plainless LAD
Driven by t11;14
-Cyclin D translocation on chrom 14
-Overexpression of Cyclin D promotes G1/S transition in cell cycle
Simple explanation of marginal zone lymphoma
Neoplastic prolif. of small B cells in the marginal zone
Associated w/ chronic inflammatory states such as hashimotos, Sjrogen syndrome, H pylori gastritis
-marginal zone ONLY forms by post-germinal center B cell
MALToma is marginal zone lymphoma in mucosal sites
Simple explanation of Burkitt lymphoma
Neoplastic prolifer. of intermediate B cells
-associated with EBV
Presents as an extranodal mass in a child or young adult
African form in Jaw
sporadic version in abdomen
What drives Burkitts lymphoma
t8;14 most common
-C-myc translocation on chromosome 14
- C-myc (oncogene) overexpression promotes cell growth
What characterizes burkitts lymphoma
High mitotic index
Starry Night appearance on smear
Explain Diffuse large B cell lymphoma
Neoplastic prolif. of large B cells that gross diffusely in sheets
-Most common NHL
-clinically aggresive
How does Diffuse large B cell lymphoma arise
Sporadically of from transformation of low-grade lymphomas (ex. follicular lymphoma)
- presents in late adulthood as enlarging lymph node or an extranodal mass
What are the NHL’s
Follicular lymphoma
Mantle cell
Marginal zone
Burkitts
Diffuse large B cell
ALL HAVE CD20
Simple explanation of Hodgkin lymphoma
Neoplastic prolifer. of Reed Sternberg cells that are CD15 and 30 positive, no CD20
RS secrete cytokines
-occasionally results in B symptoms
-attracts lymphocytes, plasma cells, macrophages, eosinophils
-may lead to fibrosis
Reactive inflammatory cells make up bulk of tumor
What are the types of plasma cell disorders
Multiple Myeloma
Monoclonal Gammapathy of Undetermined significance
Waldenstrom Macroglobulinemia
Explain Multiple Myeloma
Malignant prolif. of plasma cells in MARROW
-Most common primary malignancy of bone
-High serum IL-6; which stimulates plasma cell growth and Ig production
What are the clinical features of Multiple Myeloma
- Bone pain with hypercalcemia- Neoplasmic cells activate RANK receptors on osteaclasts–> osteoclast activity–> bone destruction (punched out lesions)
- Elevated serum protein- due to inc Ig production, monoclonality of IgG or IgA
- Increased risk of infection- due to monoclonality of only one type of Ig
- Rouleaux formation- due to inc proteinemia
- Primary AL amyloidosis- light chain proteins in serum and deposition in tissues
- Proteinuria- inc free light chain proteins (Bence Jones protein); can lead to kidney failure
Explain MGUS
Increased serum protein with M spike on SPEP, but without features of multiple myeloma
Explain Waldenstrom Macroglobulinemia
B-cell lymphoma with monoclonal IgM production
Clinical symptoms of Waldenstrom Macroglobulinemia
- General LAD; no lytic bone lesions
- Inc serum protein with M spike
- Visual and neurological symptoms due to hyperviscosity (IgM huge protein)
- Bleeding- viscous serum disrupts platelet aggregation
Types of microcytic anemia
Iron deficiency
Anemia of chronic disease
Sideroblastic anemia
Thalassemia
Types of macrocytic anemia
Folate and/ or B12 deficiency
Types of normocytic anemia
Intravascular hemolysis
-PNH
-G6PD deficiency
-IMA
-Microangiopathic HA
-Malaria
Extravascular hemolysis
-Hereditary Spherocytosis
-Sickle Cell anemia
-Hemoglobin C
Types of anemia due to underproduction
Parvovirus B19 induced
Aplastic anemia
Myelophthisic Process
Explain iron deficiency anemia
Low iron–> low heme–> low hemoglobin—> microcytic anemia
Where is iron absorbed
Duodenum
What molecule transported iron through enterocytes
ferroportin
What molecule transports iron through the blood and into hepatocytes and bone marrow macrophages
Transferrin
What molecule is bound to iron in storage
Ferritin
What is TIBC
Total iron binding capacity- measures total amount of transferrin in the blood
What kind of relationship does serum ferritin and TIBC have?
Inverse
inc ferritin, dec TIBC
dec ferritin, dec TIBC
What is Plummer Vinson syndrome
Iron deficiency anemia due to esophageal web and atrophic glossitis
presents with beefy red tongue
Explain anemia of chronic disease
Anemia associated with chronic inflammation
Causes by increased acute phase reactants (hepcidin)
dec. available iron–> dec heme–> dec hemoglobin–> microcytic anemia
What does hepcidin do?
Sequesters iron from storage by,
1) limiting iron transfer from macrophages to RBC precussors
2) Suppressing EPO production
Lab findindings for anemia of chronic disease
inc. ferritin, dec TIBC
dec. serum iron, dec. % saturation
inc. FEP (free erythrocyte protoporphyrin)
Explain sideroblastic anemia simply
Anemia due to defective protoporphyrin synthesis.
dec. protopor–> dec. heme–> dec hemoglobin–> microcytic anemia
can be congenital or acquired
-congenital: ALA synthase defect
-Acquired: B6 deficiency, alcoholism, lead poisoning
What is the mechanism of sideroblastic anemia
Iron enters mitochondria thinking its going to be added to protoporphyrin to form heme.
It doesn’t happen which leads to a build up of iron in mitochondria
Ring around the nucleus of RBCs (sideroblastic)
Lab findings for sideroblastic anemia
inc. ferritin, dec. TIBC
inc serum iron, inc % saturation
Basic principles of thalassemia
Either globin alpha or beta chain defect
dec. globin –> dec. hemoglobin –> microcytic anemia
Inherited mutation; carriers protected from plasmodium falciparum malaria
What are the normal types of Hemoglobin?
HbA(a2b2)
HbA2 (a2d2)
HbF(a2y2)
Why do thalassemia diseases vary?
Due to the # of genes are defective
low defects = asymptomatic/less severe symptoms
lots of defects = more severe defects
Explain alpha thalassemia?
Deletion of alpha chain gene(s) on chromosome 16
- 2 genes on each parents chromosomes (4 total)
-leads to microcytic anemia
1) one deletion = asymptomatic
2) two deletions: Trans deletion =less severe (africans)
Cis deletion = more severe (asians)
-mild anemia
3) three deletions: Severe anemia; Beta chains form tetramers (HbH), which damages RBC membranes
4) Four genes deletions: lethal in utero (hydrops fetalis). Gamma chains form tetramers (Hb Barts)
Explain Beta thalassemia
Point mutation in globin Beta chain genes; usually seen in africans and mediterranean descent
- two genes in total, one of each parent chromosome 11
- B+ defect in chain, Bo complete missing chain
1)B-thalassemia minor (B/B+)
- mildest form
- Hypochromic RBCs
- Dec. HbA, Inc HbA2
2) B-thalassemia major (Bo/Bo)
-most severe form
-severe anemia with increased HbF
-alpha chain precipitate and damage RBC membrane, resulting in ineffective erythropoiesis and extravascular hemolysis
-massive erythroid hyperplasia extends to skull and face bones (crew cut appearance on X ray)
-extramedullary hematopoiesis–> hepatosplenomegaly
- Inc HbA2 and HbF, NO HbA
What chromosome contains globin alpha gene
16
What chromosome contains globin beta gene
11
What causes normocytic anemia
Increased peripheral destruction or underproduction
-reticulocytes used to distinguish from micro/macrocytic anemia
Explain Hereditary Spherocytosis
Inherited defect of RBC cytoskeleton-membrane tethering proteins
-ankyrin, spectric, band 3
Membrane blebs form and lost over time
-leads to spherocytes
-spherocytes consumed by splenic macrophages–> anemia
Clinical findings of Hereditary spherocytosis
Sperocytes w/ loss of pallor
Inc RDW and MCHC
splenomegaly
Jaundice
Inc risk for aplastic crisis from parvovirus B18 infection
What kind of genetic pattern is Sickle cell anemia
Autosomal recessive
mutation in the B chain of hemoglobin
-single a.a. change :GLU—> VAL
When does sickle cell anemia typically arise
When theres two abnormal genes are present
What causes sickling in sickle cell anemia
HbS polymerizes when deoxygenated; polymers aggregate into needle like structures
What increases the risk of sickling
1)hypoxemia, dehydration and acidosis
2) dec. HbF after birth
Desickling and sickling causes what
RBC membrane damage which leads to
1)Extravascular hemolysis- reticuloendothelial system breaks down damaged RBC’s —> anemia, jaundice
2)Intravascular hemolysis- RBCs dehydrate leading to hemolysis with dec. haptoglobin and target cells
3) Massive erythroid hyperplasia
- hepatopoeisis in skull and face bones
-Extramedullary hematopoeisis–> hepatosplenomeg.
- risk of aplastic crisis from parvovirus B19 infection
Too much sickling causes vaso-occlusion, which leads to…
1)Dactylitis- swollen hands and feet due to vaso-occlusive infarcts in bones
2)Autosplenectomy
-howell-jolly bodies on smear
-inc risk of encapsulated organism infections
3)Acute chest syndrome
-vaso occlusion in pulmonary microcirculation
-presents with chest pain, shortness of breath, lung infiltrates
4) Renal papillary necrosis
5)Pain crisis
D A A R P
Difference bt sickle cell disease and sickle cell trait
Disease = both genes fucked
Trait = only one trait fucked
Lab findings of sickle cell anemia
-Sickle cells and target cells (only in disease)
-Positive Metabisulfite test (causes HbS to sickle)
-Positive HbS in electrophoresis
- Increased HbS, NO HbA
Explain simply PNH
Acquired defect in myeloid stem cells resulting in absent GPI–> renders cells susceptible to complement destruction
GPI binds to DAF, which inhibits C3 convertase activity on RBCs
No GPI = no DAF on RBCs = complement destruction = anemia
Why does destruction of RBCs/WBSCs/Platelets in PNH happen at night?
Because at night we take shallow breaths, which leads to increased CO2 which leads to acidemia, which activates complement.
What tests used for PNH
Sucrose test to screen
flow cytometry detect lack of DAF on cells
What causes death in PNH
Thrombosis due to destruction of platelets activating coagulation
Explain simply G6PD deficiency
No G6PD–> no reduced glutathione —> RBC oxidative stress –> Intravascular hemolysis—> Anemia
What kind of genetic pattern is G6PD deficiency
X-linked recessive: leads to reduced half-life of G6PD
What are the variants in G6PD deficiency
African variant- mild version = mild anemia
Mediterranean variant - Markedly reduced half life = marked intravascular hemolysis
both versions have a protective role against falciparum malaria
What happens with oxidative RBC stress in G6PD deficiency
Hb precipitates as Heinz bodies
1)Heinz bodies removed by splenic macrophages which results in bite cells
2)Intravascular hemolysis due to oxidative stress
What are the clinical presentations of G6PD deficiency
Hemoglobinuria and back pain hours after exposure to oxidative stress
Simply explain Immune Hemolytic Anemia
Antibody mediated (IgG or IgM) destruction of RBCs
IgG mediated IHA
Usually involves extravascular hemolysis
1) IgG binds to RBC in warm temp—> consumption bc splenic macrophages–>results in spherocytes
2)Associated with SLE, CLL and certain drugs
IgM mediated IHA
Usually involves intracellular hemolysis
1)IgM binds RBC and fixes complement in colder temps
2)RBCs inactivate complement, but residue C3b serves as opnosin for splenic macrophages resulting in spherocytes
3) extreme complement activation leads to intravascular hemolysis
4) associated with mononucleiosis and mycoplasma pneumoniae
What is used to diagnose IHA
Coombs test
Direct: Look for anti IgG/M in pt serum using test antibodies
Indirect: Use pts serum and mix with test RBCs to see if theres anti RBC IgG/M
What is the translocation in APL
t15;17
