Pathology Flashcards
1
Q
Immune thrombocytopenic purpura (ITP)
A
Mechanism/Etiology: Autoimmune IgG against platelet antigen GPIIb/IIIa -> autoantibodies produced in spleen by plasma cells and antibody-bound platelets are consumed in spleen by splenic macrophages –> thrombocytopenia
Presentation:
Acute- children, weeks after viral infection/vaccination; self-limited: resolves w/in weeks
Chronic- adults, usually F childbearing age; Primary or secondary to another autoimmune disorder. Can cause temporary thrombocytopenia in baby since IgG crosses placenta
Clinical features:
-mucosal and skin bleeding
Low platelet count (
2
Q
Microangiopathic hemolytic anema
A
Mechanism: Platelet microthrombi in small vessels -> platelets consumed in formation of microthrombi (thrombocytopenia) and RBCs sheared -> hemolytic anemia with schistocytes and mucosal and skin bleeding from thrombocytopenia
Seen in TTP and HUS
3
Q
Thrombotic thrombocytopenic purpura (TTP)
A
Mechanism: Decreased ADAMTS13, usually due to acquired autoantibody (adult females) -> impaired degradation of vWF multimers -> increased platelet adhesion -> microthrombi -> microangiopathic hemolytic anemia
Clinical features:
Skin and mucosal bleeding
Microangiopathic hemolytic anemia
Fever
Renal insufficiency (less prominent in TTP)
CNS abnormalities (more prominent in TTP)
Lab findings:
Low platelet count with increased bleeding time
Normal PT/PTT
Anemia w/ schistocytes
Increased megakaryocytes on bone marrow biopsy
Treatment: plasmapheresis (remove auto-abs) and corticosteroids (reduce production of auto-abs)
4
Q
Hemolytic uremic syndrome (HUS)
A
Pathogenesis: Caused by endothelial damage by drugs or infection -> increased platelet activation -> microthrombi -> microthrombocytic hemolytic anemia
-Classically in kids with E coli O157:H7 dysentery from undercooked beef –> E coli verotoxin damages endothelial cells and decreases ADAMTS13
Clinical features:
Skin and mucosal bleeding
Microangiopathic hemolytic anemia
Fever
Renal insufficiency (more prominent in HUS)
CNS abnormalities (less prominent in HUS)
Lab findings:
Low platelet count with increased bleeding time
Normal PT/PTT
Anemia w/ schistocytes
Increased megakaryocytes on bone marrow biopsy
5
Q
Bernard-Soulier syndrome
A
Pathogenesis: GP1b deficiency -> impaired platelet adhesion to vWF
Clinical features: -mucosal and skin bleeding -normal/slightly low platelet count -increased bleeding time -blood smear shows enlarged platelets No agglutination on ristocetin (vWF agonist) cofactor assay (Note: also seen with vWF disease)
6
Q
Glanzmann thrombasthenia
A
pathogenesis: Genetic GPIIb/IIIa deficiency-> platelet aggregation impaired
Clinical features
- mucosal and skin bleeding
- normal platelet count
- increased bleeding time
- Agglutination on ristocetin (vWF agonist) cofactor assay
Note: analogous to GpIIb/IIIa inhibitory actions of Abciximab, eptifibatide and tirofiban
7
Q
What are the three activating requirements for the coagulation cascade?
A
- exposure to activating substance
- tissue thromboplastin activates VII (extrinsic)
- subendothelial collagen activates XII (intrinsic) - phosholipid surface of platelets
- calcium (from platelet dense granules)
8
Q
What are common symptoms of disorders of secondary hemostasis (coagulation factor abnormalities)
A
deep tissue bleeding into muscles and joints (hemarthrosis) and rebleeding after surgical procedures
9
Q
Hemophilia A, B, C
A
Hemophilia A (most common) -XR or de novo mutation -> factor VIII deficiency Hemophilia B - XR, Factor IX deficiency Hemophilia C- AR, Factor XI deficiency
Clinical features:
- macrohemorrhage in hemophilia- hemarthroses, easy bruising, bleeding after procedures
- Increased PTT, normal PT
- decreased coagulation factor
- normal platelet count and bleeding time
Treatment: desmopressin (increases release of vWF and factor VIII from endothelial cells) + recombinant missing factor
10
Q
Coagulation factor inhibitor
A
Antibody against coagulation factor- anti-FVIII most common
-Clinically similar to hemophilia A but PTT does NOT correct when mixed with normal plasma, unlike hemophilia A which does correct
11
Q
Von Willebrand Disease
A
*Most common inherited coagulation disorder
Pathogenesis: most commonly AD genetic vWF deficiency -> impaired platelet adhesion and decreased FVIII (vWF stabilizes FVIII)
Clinical features:
- Mild mucosal and skin bleeding
- Hx of mucosal bleeding- gingival, epistaxis and/or menorrhagia
- increased bleeding time
- increased PTT (low FVIII), normal PT
- *Abnormal ristocetin (induces platelet agglutination) test –> lack of vWF -> impaired agglutination -> abnormal test
Treatment: desmopressin (ADH analog) increases vWF release from Weibel-Palade bodies
12
Q
Vitamin K deficiency
A
Normal physiology: Vitamin K activated by epoxide reductase; activated vitamin K gamma carboxylases factors II, VII, IX, X, and proteins C, S (intrinsic and extrinsic)
Deficiency etiology:
Newborns- lack GI bacteria that normally synthesize vitamin K; give vitamin K prophylactically at birth
Long-term antibiotic therapy - decreases vitamin K producing bacteria in GI tract
Malabsorption of fat soluble vitamins
Clinical features:
Increased PT and PTT
13
Q
Heparin-induced thrombocytopenia (HIT)
A
Heparin forms complex with platelet factor 4
Autoantibodies against Heparin-PF4 complex:
- cause spleen to consume platelets -> thrombocytopenia
- fragments of destroyed platelets activate other platelets -> thrombosis
Treatment: discontinue and give another anti-coagulant, but NOT coumadin due to worry of skin necrosis
14
Q
Disseminated intravascular coagulation (DIC)
A
Pathogenesis: Pathologic complete activation of coagulation cascade-> widespread microthrombi –> thrombocytopenia and ischemia and infarction
Etiology: usually secondary
- Obstetric complications (tissue factor in amniotic fluid)
- Sepsis (especially E. coli or N. meningitidis) exotoxins and cytokines induce tissue factor production
- Adenocarcinoma
- Acute promyelocytic leukemia (primary granules activate coag.)
- Rattlesnake bite
Clinical features:
- superficial bleeding, especially from IV sites
- low platelet count
- increased PT/PTT
- decreased fibrinogen (whole coag cascade activated)
- **Elevated D-dimer (from splitting of cross-linked fibrin)
Treatment:
transfuse blood products and cryoprecipitate
15
Q
Normal fibrinolysis
A
- tPA converts plasminogen to plasmin
- Plasmin: 1) cleaves fibrin and fibrinogen, 2) destroys coagulation factors, 3) blocks platelet aggregation
- alpha2-antiplasmin inactivates plasmin
16
Q
Fibrinolysis disorders
A
Pathogenesis: overactivity of plasmin -> excessive cleavage of fibrinogen -> increased bleeding
Etiology:
Radical prostatectomy: urokinase activates plasmin
Cirrhosis - reduced production of alpha2-antiplasmin
Lab findings:
- Increased PT/PTT
- Increased bleeding time with normal platelet count
- Increased fibrinogen split products WITHOUT D-dimers
Treatment: aminocaproic acid -> blocks conversion of plasminogen to plasmin
17
Q
Histologic features of DVT
A
- lines of Zahn (alternating layers platelets/fibrins and RBCs)
- attachement to vessel wall
18
Q
What mechanisms by endothelial cells prevent thrombosis?
A
- block exposure to subendothelial collagen and tissue factor
- produce PGI2 (prostacyclin) and NO -> vasodilate and inhibit platelet aggregation
- Secrete heparin-like molecules which stimulate antithrombin III (ATIII)
- Secrete tPA- converts plasminogen to plasmin
- Secrete thrombomodulin -> redirect thrombin to activate protein C -> inactivates FV and FVIII
19
Q
How do high levels of high levels of homocysteine cause endothelial cell damage?
A
- vitamin B12 and folate deficiency -> decreased conversion of homocysteine to methionine –> high homocysteine levels -> build up causes endothelial damage
- Cystathionine beta synthase deficiency -> Homocystinuria
- thrombosis, retardation, lens dislocation, long slender fingers
20
Q
Protein C or S deficiency
A
AD deficiency
Pathogenesis: Decreased protein C and S -> increased FV and FVIII activation -> increased coagulation
Clinical features:
- increased venous and arterial clots
- increased risk for warfarin skin necrosis since initial stage of therapy causes deficiency of C and S relative to other factors
21
Q
Factor V Leiden
A
*Most common inherited hypercoaguable state in caucasians
mutated factor V lacks cleavage site for deactivation by proteins C and S –> overactive factor V –> hypercoaguable state
22
Q
Prothrombin 20210A (gene mutation)
A
inherited point mutation in prothrombin 3’ untranslated region -> increased gene expression -> increased thrombin -> thrombosis
23
Q
Antithrombin deficiency
A
Inherited ATIII deficiency decreases protective effect of heparin-like molecules and increase risk of thrombus
-can be acquired in renal failure/nephrotic syndrome: ATIII loss in urine -> decreased inhibition of IIa and Xa
Clinical features:
- PTT does NOT rise with standard heparin dose
- High doses of heparin required to activate the limited ATIII then coumadin given to maintain anticoagulation state
24
Q
Types of embolism
A
Thromboembolism most common
- Atherosclerotic embolus
- Fat embolus: associated with bone fractures and soft tissue trauma; see petechiae on skin over the chest and bone marrow elements in vessel
- Gas embolus: decompression sickness with divers (joint/muscle pain and dyspnea), Caisson disease (multifocal ischemic necrosis of bone), laparascopic surgery
- Amniotic fluid embolus during labor/delivery; characterized by squamous cells and keratin debris from fetal skin in embolus
25
Microcytic anemia
Anemia with MCV 'extra' division --> smaller than normal RBCs
Hemoglobin deficiency can be caused by deficiency in: iron, protoporphyrin (make up heme) or globin
Causes:
1. iron deficiency anemia (late stage)
2. anemia of chronic disease (late)
3. sideroblastic anemia (decreased protoporphyrin)
4. thalassemia (decreased globin)
5. lead poisoning (decreased protoporphyrin)
26
Iron deficiency anemia
Pathogenesis: low Fe -> low heme -> low Hb -> microcytic anemia
-Most common form of anemia
Causes:
- infants- dietary lack of Fe in breastmilk
- kids- poor diet
- adults (20-50yo) - peptic ulcer disease (M) and menorrhagia or pregnancy (F)
- elderly - colon polyps/cancer (West); hookworm (Ancylostoma and Necator) in developing world
- Gastrectomy -> decreased H+ -> less iron in Fe2+ state -> less absorption -> anemia
Stages of iron deficiency:
1. storage iron depleted - low ferritin, high TIBC
2. serum Fe depleted - low serum Fe, low % sat
3. Normocytic anemia - bone marrow makes fewer normal sized RBCs
4. microcytic hypochromic anemia - bone marrow makes smaller and fewer RBCs
- increased RDW
- Increased free erythrocyte protoporphyrin (FEP)
Clinical features: koilonychia (spoon nails) and pica and anemia symptoms
27
Plummer-Vinson syndrome
iron deficiency anemia + esophageal web + atrophic glossitis
28
Anemia of chronic disease
Pathogenesis: chronic inflammation or cancer -> increased acute phase reactants from liver including hepcidin -> hepcidin sequesters iron into storage:
1. limit Fe transfer from macrophages to erythroblasts
2. suppress EPO production
- -> prevent bacteria getting iron -> low Fe -> low heme -> low Hb -> normocytic anemia -> microcytic anemia
Lab findings:
MCV
29
Sideroblastic anemia
Defect in protoporphyrin synthesis -> microcytic anemia
Protoporphyrin deficiency-> iron trapped in mitochondria -> Iron-laden mitochondria form ring around nucleus --> ringed sideroblasts
Congential defect:
- X-linked ALAS defect (rate-limiting step)
Acquired:
- alcoholism (mitochondria poison)
- lead poisoning - inhibits ALAD and ferrochelatase
- vitamin B6 deficiency (isoniazid treatment toxicity)
30
alpha-thalassemia
alpha-globin gene deletion (chromosome 16) - 4 total genes
2 genes deleted - mild anemia with increased RBC count
- cis deletion (2 genes on same chromosome deleted) - Asians, risk of severe thalassemia in offspring
- trans deletion - Africans
3 genes deleted- severe anemia, beta tetramers (HbH) damage RBCs are seen on electrophoresis
4 genes deleted - hydrops fetalis- fatal in utero; gamma chains form tetramers (Hb Barts)
31
beta-thalassemia
beta-globin gene point-mutation in splice sites (chromosome 11) only 2 genes
-prevalent in African and Mediterranean populations
beta-thalassemia minor (beta/beta+) - mild form
- asymptomatic w increased RBCs
- microcytic hypochromic RBCs and target cells
- HbA2 >3.5%
beta-thalassemia major (beta0/beta0) - severe
- severe anemia few months post birth
- alpha chains form tetramers and damage RBCs -> extravascular hemolysis
- erythroid hyperplasia -> hematopoiesis into skull w/ "crew cut" appearance on x-ray and into facial bones w/ "chipmunk facies"
- risk aplastic crisis w parvovirus B19
- chronic transfusions necessary (risk of hemochromatosis)
- smear: microcytic hypochromic RBCs w target cells and nucleated RBCs
- electrophoresis: HbA2 and HbF w/ no HbA
32
Causes of megaloblastic macrocytic anemia
anemia with MCV >100fL due to impairment of DNA pre-cursor synthesis
- folate or vitamin B12 deficiency
- orotic aciduria
33
Folate deficiency
deficiency develops w/in months. Absorbed in jejunum
Causes:
- poor diet (alcoholics and elderly)
- increased demand (preg, cancer, hemolytic anemia)
- folate antagonists (methotrexate, TMP, phenytoin)
Clinical features:
- Macrocytic RBCs and hypersegmented PMNs
- Glossitis
- decreased serum folate
- increased homocysteine (increased risk for thrombosis)
- NORMAL methylmalonic acid (contrast w B12 deficiency)
- NO neuro symptoms
34
B12 (cobalamin) deficiency
Takes years to develop. B12 needs pancreatic protease be able to bind to IF. Absorbed in ileum
Causes:
- insufficient intake (vegans)
- malabsorption (Crohn disease)
- pancreatic insufficiency
- pernicious anemia* most common cause
- Diphyllobothrium latum (fish tapeworm)
- gastrectomy
Clinical findings:
- Macrocytic RBCs w hypersegmented PMNs
- glossitis
- Increased homocysteine
- Increased methylmalonic acid (MMA)
- Neuro symptoms: subacute combined degeneration of spinal cord due to build up of MMA in myelin
35
Pernicious anemia
autoimmune destruction of parietal cells -> intrinsic factor deficiency -> B12 deficiency -> megaloblastic anemia
36
Hereditary spherocytosis
Pathogenesis: Inherited defect of RBC cytoskeleton membrane tethering proteins (ankyrin, band 3.1, protein 4.2, spectrin) -> membrane blebs -> spleen removes blebbed membrane --> RBCs become round spherocytes --> consumed by splenic macrophages -> normocytic anemia
Clinical features:
- spherocytes w loss of central pallor
- increased RDW and MCHC
- normal to low MCV
- osmotic fragility test (+)
- splenomegaly, jaundice and increase risk gallstones
- increased risk aplastic crisis w parvovirus B19
Treatment: splenectomy -> will still get spherocytes and then Howell-Jolly bodies, but anemia resolves
37
Orotic aciduria
Inability to convert orotic acid -> UMP due to defect in UMP synthase
-Autosomal recessive
Clinical features:
- failure to thrive, developmental delay and megaloblastic anemia refractory to folate and B12
- Orotic acid in urine
- NO hyperammonemia (unlike OTC deficiency which also increases orotic acid)
Treatment: UMP to bypass mutated enzyme
38
Nonmegaloblastic macrocytic anemia
DNA synthesis unimpaired and MCV>100fL
Causes: alcoholism, liver disease, hypothyroidism, reticulocytosis
39
Sickle cell anemia - what is the mutation
AR mutation in beta chain of Hb glutamic acid (hydrophilic) is changed to valine (hydrophobic)
40
What is the pathogenesis of sickle cell anemia?
HbS polymerizes when deoxygenated
low O2, high altitude or acidosis precipitates sickling -> anemia and vaso-occlusive disease
41
What treatment increases HbF?
hydroxyurea
42
What are the complications of sickle cell anemia?
RBC damage
- extravascular hemolysis -> anemia, jaundice, bilirubin gallstones
- intravascular hemolysis (less) -> target cells, decreased haptoglobin
Erythroid hyperplasia
- hematopoesis in skull - 'crewcut' appearance
- hematopoesis in facial bones - chipmunk face
- risk of aplastic crisis w parvovirus B19
Vaso-occlusion
-Dactylitis: swollen hands and feet due to infarcts in bones; common presenting infants
- Autosplenectomy: small fibrotic spleen
- ->risk infection w Strep pneumo, H influenzae (common death in kids)
- ->risk Salmonella osteomyelitis
- ->Howell-Jolly bodies
- Acute chest syndrome: vaso-occlusion in pulm microcirculation; usually precipitated by pneumonia (common cause of death in adults)
- pain crisis
- Renal papillary necrosis: hematuria and proteinuria
43
How can sickle cell trait be diagnosed?
Metabisulfite screen -> causes any amount of HbS to sickle --> (+) in both disease and trait
Hb electrophoresis
44
Hemoglobin C
AR mutation in beta chain: glutamic acid-> lysine
- mild anemia w extravascular hemolysis
- HbC crystals on smear
45
Pyruvate kinase deficiency
AR. Defect in pyruvate kinase -> decrease ATP -> rigid RBCs
-hemolytic anemia in newborn
46
Paroxysmal nocturnal hemoglobinuria (PNH)
Acquired defect in myeloid stem cells -> absent GPI -> cannot secure DAF -> RBCs susceptible to complement damage
-Intravascular hemolysis occurs often at night due to shallow breathing -> increased CO2 -> respiratory acidosis -> activation of complement -> RBC, WBC and platelet lysis --> hemoglobinuria in morning
TRIAD: Coombs (-) hemolytic anemia, pancytopenia and venous thrombosis (common cause of death)
Labs: CD55/59 (-) RBCs on flow cytometry
Increased risk of AML
Treatment: eculizumab (terminal complement inhibitor)
47
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
XR reduced half-life of G6PD --> increased susceptibility to oxidative stress
decreased G6PD -> decreased NADPH -> decreased reduction of glutathione -> oxidative injury by H2O2 -> intravascular hemolysis
African variant- mild reduction
Mediterranean variant - markedly reduced half-life of G6PD
-protective against falciparum malaria
Presentation: back pain and hemoglobinuria hours after oxidative stress exposure
Oxidative stress precipitates Hb as Heinz bodies which are removed by splenic macrophages -> bite cells
Causes of oxidative stress:
- infections
- drugs (primaquine, sulfa drugs, dapsone)
- fava beans
48
Immune hemolytic anemia - IgG mediated
IgG mediated disease
- extravascular hemolysis
-bind RBCs in warm temp of central body (warm agglutinin) -> antibody coated RBC membrane consumed by splenic macrophages -> spherocytes
- Associated with SLE (most common), CLL and some drugs (penicillin and cephalosporins)
- drug (penicillin) can attach to membrane and then ab binds to drug-membrane complex
- drug may directly induce production of autoantibodies that bind RBCs (methyldopa)
49
Immune hemolytic anemia - IgM mediated
IgM mediated disease
-extravascular hemolysis
- bind RBCs in cold temp of extremities (cold agglutinin) -> compliment binds antibody coated RBC membrane --> residual C3b serves as opsonin to be consumed by splenic macrophages -> spherocytes
- Extreme compliment activation can cause intravascular hemolysis
Associated with M. pneumoniae and infectious mono
50
Diagnosis of immune hemolytic anemia
Direct Coombs test -> confirms presence of ab or complement-coated RBC
Indirect Coombs test -> confirms presence of abs in patient serum
51
Anemia due to underproduction (non-hemolytic)
low retic count
Etiologies:
Renal failure (decreased EPO)
Damage to bone marrow precursor cells-
Parvovirus B19 - infects progenitor cells and halts erythropoiesis; significant anemia if preexisting marrow stress
Aplastic anemia
52
Aplastic anemia
Pathogenesis: damage to hematopoietic stem cells -> pancytopenia
Due to:
- radiation and drugs (benzene, chloramphenicol, alkylating agents, antimetabolites)
- viral agents (parvovirus B19, EBV, HIV, HCV),
- Fanconi anemia (DNA repair defect)
- Idiopathic
Biopsy: empty, fatty marrow
Treatment: transfusions and marrow-stimulating factors (EPO, GM-CSF, G-CSF)
- immunosuppression as idiopathic can be caused by abnormal Tcell activation
- bone marrow transplantation last resort
53
Lead poisoning
Inhibits ferrochelatase and ALA dehydratase -> decreased heme synthesis and increased RBC protoporphyrin -> microcytic anemia
Inhibits rRNA degradation -> RBCs retain rRNA (basophilic stippling)
Findings (LEAD):
Lead lines on gingivae (Burton lines) and on metaphyses of long bones on xray
Encephalopathy and Erythrocyte basophilic stippling
Abdominal colic and sideroblastic Anemia
Drops- wrist and foot drop
Dimercaprol and EDTA 1st line treatment; Succimer used for chelation for kids
54
Acute intermittent porphyria
Affected enzyme: Porphobilinogen deaminase
Accumulated substrate: Porphobilinogen, delta-ALA, coporphobilinogen (port-wine colored urine)
```
Presenting symptoms:
-Painful abdomen
-Port wine colored urine
-Polyneuropathy
-Psych disturbances
-Precipitated by drugs (cytochrome P450 inducers), alcohol and starvation
(NO RASH OR PHOTOSENSITIVITY)
```
Treatment: glucose and heme (inhibit ALA synthase)
55
Porphyria cutanea tarda
Affected enzyme: Uroporphyrinogen decarboxylase
Accumulated substrate: Uroporphyrin (tea-colored urine)
Presenting symptoms: Blistering cutaneous photosensitivity** Most common porphyria
56
Leukopenia
Neutropenia -> decreased circulating PMNs
Causes:
1. Drug toxicity (chemo w/ alkylating agents)- damage to stem cells
2. Severe infection - increased movement of PMNs into tissue and decreased circulating
Treatment: GM-CSF or G-CSF boost granulocyte production
Lymphopenia -> decreased circulating lymphocytes
Causes:
1. immunodeficiency (ex DiGeorge or HIV)
2. High coritsol state -> apoptosis of lymphocytes
3. Autoimmune destruction (ex SLE)
4. Whole body radiation - lymphocytes highly sensitive
57
Neutrophilic leukocytosis
increased circulating PMNs
Causes:
1. bacterial infection or tissue necrosis- release of marginated pool and bone marrow PMNs including immature cells (Left shift) *immature cells characterized by DECREASED CD16 (Fc receptors)
2.High cortisol state- impaired leukocyte adhesion -> release of marginated pools
58
Monocytosis
increased monocytes
Causes: chronic inflammatory states and malignancy
59
Eosinophilia
increased circulating eosinophils
Causes:
allergic rxns
parasitic infections
Hodgkin lymphoma (increased IL-5 production)
60
Basophilia
increased circulating basophils
Causes: CML (Chronic Myeloid Leukemia)
61
Lymphocytic leukocytosis
increased circulating lymphocytes
Causes:
1. viral infections -> T lymphocyte hyperplasia to respond to virus
2. Bordetella pertussis infection - Bacteria produces lymphocytosis-promoting factor -> prevents lymphocytes from leaving blood to enter LN
62
Infectious Mononucleosis
EBV infection (CMV less common) via saliva -> infects oropharynx (pharyngitis), liver (hepatitis) and B cells -> lymphocytic leukocytosis
CD8+ T cell response causes:
- LAD
- Splenomegaly due to T-cell hyperplasia in periarterial lymphatic sheath (PALS)
- High WBC count w atypical lymphocytes (reactive CD8+ Tcells) -> enlarged nucleus and abundant cytosol
```
Monospot test (+) -> EBV
Monospot test (-) -> CMV
```
Complications:
1. Increased risk splenic rupture -> avoid contact sports
2. Rash if exposed to ampicillin
3. Dormancy of virus -> increased risk of recurrence and B-cell lymphoma
63
Acute leukemia - general characteristics
Neoplastic proliferation of blasts; Defined as >20% blasts in bone marrow
Blasts crowd out normal cells -> 'acute' presentation of anemia (fatigue), thromobcytopenia (bleeding) or neutropenia (infection)
Blasts: large, immature cells with little cytoplasm and ;punched out' nucleoli
64
Acute lymphoblastic leukemia (ALL)
Neoplastic accumulation of lymphoblasts (>20%) in bone marrow
Characterized: (+)TdT - DNA polymerase; absent in myeloid blasts and mature lymphocytes
Commonly arises in kids; associated with Down syndrome in kids OLDER than 5 years old
Sub-classified into B-ALL and T-ALL
65
B-ALL
most common type of ALL
TdT+ lymphoblasts that express CD10, CD19 and CD20
Excellent response to chemo; requires prophylaxis to scrotum and CSF due to blood barrier
Prognosis based on cytogenic abnormalities:
t(12;21)- good prognosis; common in children
t(9;22)- poor prognosis; common in adults (Philadelphia+ ALL)
66
T-ALL
TdT+ lymphoblasts expressing markers ranging from CD2-8
- Teenagers
- Thymic (mediastinal) mass --> called Acute Lymphoblastic LymphOMA
67
Acute myeloid leukemia (AML)
Neoplastic accumulation of immature myeloid cells (>20%) in marrow
Characterized by +MPO (myeloperoxidase) staining --> Auer rods (crystalized MPO)
- Commonly in older adults (50-60yo)
- Sub-classified into: Acute promyelocytic leukemia, acute monocytic leukemia and acute megakaryoblastic leukemia
- AML may arise from pre-existing dysplasia, especially exposure to alkylating agents or RT
- -> myelodysplastic syndromes: cytopenias, hypercellular marrow, abnormal maturation of cells and increased blasts (
68
Acute promyelocytic leukemia
M3 AML subtype
Characterized by t(15;17) translocation -> RAR (retinoic acid receptor) on chromosome 17 to 15 -> RAR disruption blocks maturation -> blasts accumulate
- Abnormal promyelocytes have many primary granules -> increased risk DIC*
- Treat with all-trans-retinoic acid (ATRA, vitamin A derivative) -> binds to RAR and causes maturation of blasts to PMNs -> die
69
Acute monocytic leukemia
Proliferation monoblasts -> infiltrate gums
-LACK MPO
70
Acute megakaryocytic leukemia
Proliferation of megakaryoblasts; LACK MPO
-Associated with Down syndrome, kids YOUNGER than 5 yo
71
Chronic leukemia - general
neoplastic proliferation of MATURE circulating lymphocytes
-insidious onset and seen in older adults
72
Chronic lymphocytic leukemia (CLL)
Proliferation of naive B cells
-Most common leukemia
Clinical features:
- increased lymphocytes expressing CD5**(usually on Tcells) and CD20
- smudge cells on blood smear
- if lymph nodes involved-> generalized LAD-> called small lymphocytic lymphoma
Complications:
1. hypogammaglobinemia (most common cause death)
2. Autoimmune hemolytic anemia (naive B cells make poor Igs)
3. Transformation to diffuse large B-cell lymphoma (Richter transformation) - enlarging LN or spleen
73
Hairy cell leukemia
Proliferation of mature B cells with hairy cytoplasmic processes
Clinical features:
- TRAP(+)
- Splenomegaly (accumulation in red pulp)
- "dry tap" on bone marrow aspiration (marrow fibrosis)
- LAD usually ABSENT
Treatment: responds to 2-CDA (cladribine) adenosine deaminase inhibitor
74
Adult T-cell leukemia/lymphoma (ATLL)
Neoplastic proliferation of mature CD4+ T-cells
-associated with HTLV-1 and IV drug use; seen commonly in Japan and Caribbean
Clinical features:
- Rash (skin infiltration)
- Generalized LAD
- HSM
- Lytic (punched-out) bone lesions with hypercalcemia
75
Mycosis Fungoides
Neoplastic proliferation of mature CD4+ T-cells
Clinical features:
infiltrate skin --> rash, plaques, nodules
Aggregates of neoplastic cells in epidermis= Pautrier microabscesses
-spread to blood -> Sezary syndrome (cerebriform nuclei seen on smear)
76
What are general complications that can occur in myeloproliferative disorders (MPD)
Complications:
Increased risk hyperuricemia and gout (high cell turnover -> increased uric acid)
Progression to marrow fibrosis or transformation to acute leukemia
77
Chronic myeloid leukemia (CML)
Neoplastic proliferation of mature myeloid cells, especially granulocytes --> BASOPHILS characteristically increased
Philadelphia chromosome t(9;22) -> BCR-ABL fusion protein w increased tyrosine kinase activity; mutation in pluripotent stem cell!
Clinical features:
- leukocyte alkaline phosphatase LAP (-) stain
- Splenomegaly; enlarging spleen suggests accelerated phase which can transform to AML (2/3 of cases) or ALL (1/3 cases)
Treatment: imatinib - blocks tyrosine kinase activity
78
How is CML distinguished from leukemoid reaction?
1. LAP stain: granulocytes in leukemoid rxn are LAP (+), CML is LAP (-)
2. Increased basophils in CML, not in leukemoid rxn
3. t(9;22) in CML, not in leukomoid
79
Polycythemia vera
Proliferation of mature myeloid cells, especially RBCs (granulocytes and platelets also increased)
*Associated with JAK2 kinase mutation-> cytoplasmic tyrosine kinase that phosphorylates EPO receptor to initiate downstream signaling*
Clinical symptoms due to hyperviscosity of blood from high # of RBCs:
1. blurry vision and HA
2. venous thrombosis risk (most common cause of Budd chiari syndrome: hepatic vein thrombosis)
3. Flushed face
4. Itching after bathing (histamine release from mast cells)
Treatment: phlebotomy; second line: hydroxyurea
80
How is polycythemia vera differentiated from reactive polycythemia or ectopic EPO production?
High RBCs
1. High EPO
a. low SaO2 -> reactive polycythemia to lung disease or high altitude
b. normal SaO2 -> ectopic EPO from renal cell CA
2. Low EPO and normal SaO2 -> P. vera
81
Essential thrombocythemia
Proliferation of mature myeloid cells, especially platelets (RBCs and granulocytes also increased)
*Associated with JAK2 kinase mutation*
Symptoms- increased bleeding and/or thrombosis
Rarely progresses to marrow fibrosis or acute leukemia unlike other MPDs
No significant risk for hyperuricemia/gout b/c not turing over nuclear material, just cytoplasm
82
Myelofibrosis
Proliferation of mature myeloid cells, especially megakaryocytes
-Excess platelet-derived growth factor (PDGF) produced -> marrow fibrosis
Clinical features:
1. splenomegaly
2. tear drop RBCs, nucleated RBCs and immature granulocytes on smear (leukoerythroblastic smear)
3. increased risk infection, thrombosis and bleeding
83
Causes of lymphadenopathy
Painful LAD- acute infection
Painless LAD- chronic inflammation, metastatic carcinoma or lymphoma
LN enlargement=hyperplasia
1. follicular hyperplasia (B-cell region)
- RA, early HIV infection
2. paracortex hyperplasia (T-cell region)
- viral infections (infectious mono)
3. hyperplasia of sinus histiocytes
- draining tissue with cancer
84
Lymphoma: Hodgkin vs Non-Hodgkin
Non-Hodgkin lymphoma
-more common (60%)
Mass comprised of lymphoid cells (malignant cell)
Presentation: painless LAD, usually late adulthood
Spread: diffuse, extranodal
Leukemic phase: Yes
Hodgkin lymphoma
-less common (40%)
Mass comprised of predominantly reactive cells; malignant cell is Reed-Sternberg cell
Presentation: painless LAD with B symptoms; usually young adult
Spread: continguous; rarely extranodal
Leukemic phase: No
85
Follicular lymphoma
Neoplastic proliferation of small B cells (CD20+)
-presents late adulthood w/ painless 'waxing and waning' LAD
t(14;18)-> BCL2 (chromosome 18) inhibits apoptosis; Ig heavy chain (chromosome 14)
Features:
- form follicle-like nodules that disrupt normal LN architecture
- small cleaved cells w/out nucleoli and larger non-cleaved cells w/ multiple nucleoli
- lack tingible body macrophages in germinal centers
- Bcl2 expression
- Monoclonality (ratio of kappa to lambda light chain ~20:1 whereas normal 3:1)
86
Mantle cell lymphoma
Neoplastic proliferation of small B cells (CD20+) that expands into mantle zone (immediately adjacent to follicle)
-presents late adulthood w/ painless LAD
t(11;14)-> Cyclin D1 (chromosome 11) promotes G1/S transition; translocates with Ig heavy chain (chromosome 14)
87
Marginal zone lymphoma
Neoplastic proliferation of small B cells (CD20+) into marginal zone (area formed by post-germinal center Bcells)
-associated with chronic inflammatory states: Hashimoto thyroiditis, Sjogren syndrome, H.pylori gastritis
MALToma is marginal zone lymphoma in mucosal sites
-gastric MALToma may regress w treatment of H.pylori
88
Burkitt lymphoma
Neoplastic proliferation of intermediate sized B cells (CD20+) - associated with EBV
-presents as extranodal mass in child or young adult
African form: jaw
Sporadic form: abdomen
t(8;14)-> c-myc (chromosome 8) oncogene promotes cell growth; translocated to Ig heavy chain (chromosome 14)
Histology: 'starry-sky' appearance, high mitotic index
89
Diffuse large B-cell lymphoma
Neoplastic proliferation of large B cells (CD20+) that grow diffusely in sheets
-Most common type of Non-Hodgkin lymphoma
Arises sporadically or from transformation of low-grade lymphoma
-clinically aggressive: not well differentiated
Presentation: enlarging LN or extranodal mass late in adulthood
90
Hodgkin lymphoma
Neoplastic proliferation of Reed-Sternberg (RS) cells --> large B cells w multilobed nuclei and prominent nucleoli 'owl-eyed' nuclei
CD15+ and CD30+
Presentation:
B symptoms due to RS cells secreting cytokines that attract reactive inflammatory cells which make up bulk of tumor; may lead to fibrosis
Subtypes:
1. Nodular sclerosis
- most common, enlarging cervical or mediastinal LN in young F
- LN divide by bands of sclerosis; RS present in lacunar cells
2. Lymphocyte-rich
- Best prognosis
3. Mixed cellularity
- Associated with eosinophilia (IL-5 recruits)
4. Lymphocyte depleted
- Worst prognosis; usually in elderly and HIV+
91
Multiple myeloma
Malignant proliferation of plasma cells in marrow
* Most common primary malignancy of bone; metastatic cancer most common overall
* High IL-6 may be present -> stimulates plasma cell growth and Ig production
Clinical features:
1. bone pain w hypercalcemia- neoplastic plasma cells activate RANK on osteoclasts-> bone damage --> 'punched out' lytic bone lesions on x-ray
2. Elevated serum protein (increased Ig production)
3. M spike on SPEP; due to monoclonal IgG or IgA
4. Risk of infection since lack antigenic diversity -> infection is most common cause of death
5. Rouleaux formation - piled up RBCs on smear (increased protein decreases charge btwn RBCs)
6. Increased light chains circulating:
- in blood-> Primary AL amyloidosis
- in urine -> Bence Jones protein
- in kidney -> renal damage
92
Monoclonal gammopathy of undetermined significance (MGUS)
M spike on SPEP but other features of multiple myeloma absent
-common in elderly; 1% of individuals with MGUS go on to multiple myeloma
93
Waldenstrom Macroglobulinemia
B-cell lymphoma w monocolonal IgM production (pentamer)
Clinical features:
1. generalized LAD w/out lytic bone lesions
2. M spike comprised of IgM
3. Visual and neuro defects due to serum hyperviscosity (retinal hemorrhage or stroke)
4. Bleeding - viscous serum -> defective plt aggregation
Complications treated w/ plasmapheresis
94
Langerhans cell histiocytosis
Neoplastic proliferation of Langerhans cells
Langerhans cells: specialized dendritic cells in skin; derived from monocytes; present antigen to naive T cells
Characteristics:
Birbeck (tennis racket) granules on EM
(+) CD1a and S100
- can present with rash
- Eosinophilic granuloma subtype can cause pathologic fractures in adolescent (on Ddx w/ osteosarcoma)
