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Heme/Onc > Pathology > Flashcards

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 (

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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

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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)

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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

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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)
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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

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7
Q

What are the three activating requirements for the coagulation cascade?

A
  1. exposure to activating substance
    - tissue thromboplastin activates VII (extrinsic)
    - subendothelial collagen activates XII (intrinsic)
  2. phosholipid surface of platelets
  3. calcium (from platelet dense granules)
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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

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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

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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

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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

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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

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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

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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

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15
Q

Normal fibrinolysis

A
  1. tPA converts plasminogen to plasmin
  2. Plasmin: 1) cleaves fibrin and fibrinogen, 2) destroys coagulation factors, 3) blocks platelet aggregation
  3. alpha2-antiplasmin inactivates plasmin
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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

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17
Q

Histologic features of DVT

A
  1. lines of Zahn (alternating layers platelets/fibrins and RBCs)
  2. attachement to vessel wall
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18
Q

What mechanisms by endothelial cells prevent thrombosis?

A
  1. block exposure to subendothelial collagen and tissue factor
  2. produce PGI2 (prostacyclin) and NO -> vasodilate and inhibit platelet aggregation
  3. Secrete heparin-like molecules which stimulate antithrombin III (ATIII)
  4. Secrete tPA- converts plasminogen to plasmin
  5. Secrete thrombomodulin -> redirect thrombin to activate protein C -> inactivates FV and FVIII
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19
Q

How do high levels of high levels of homocysteine cause endothelial cell damage?

A
  1. vitamin B12 and folate deficiency -> decreased conversion of homocysteine to methionine –> high homocysteine levels -> build up causes endothelial damage
  2. Cystathionine beta synthase deficiency -> Homocystinuria
    - thrombosis, retardation, lens dislocation, long slender fingers
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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
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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

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22
Q

Prothrombin 20210A (gene mutation)

A

inherited point mutation in prothrombin 3’ untranslated region -> increased gene expression -> increased thrombin -> thrombosis

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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
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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
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25
Q

Microcytic anemia

A

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)
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26
Q

Iron deficiency anemia

A

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

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27
Q

Plummer-Vinson syndrome

A

iron deficiency anemia + esophageal web + atrophic glossitis

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28
Q

Anemia of chronic disease

A

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

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29
Q

Sideroblastic anemia

A

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)

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30
Q

alpha-thalassemia

A

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)

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31
Q

beta-thalassemia

A

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
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32
Q

Causes of megaloblastic macrocytic anemia

A

anemia with MCV >100fL due to impairment of DNA pre-cursor synthesis

  • folate or vitamin B12 deficiency
  • orotic aciduria
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33
Q

Folate deficiency

A

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
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34
Q

B12 (cobalamin) deficiency

A

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
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35
Q

Pernicious anemia

A

autoimmune destruction of parietal cells -> intrinsic factor deficiency -> B12 deficiency -> megaloblastic anemia

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36
Q

Hereditary spherocytosis

A

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

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37
Q

Orotic aciduria

A

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

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38
Q

Nonmegaloblastic macrocytic anemia

A

DNA synthesis unimpaired and MCV>100fL

Causes: alcoholism, liver disease, hypothyroidism, reticulocytosis

39
Q

Sickle cell anemia - what is the mutation

A

AR mutation in beta chain of Hb glutamic acid (hydrophilic) is changed to valine (hydrophobic)

40
Q

What is the pathogenesis of sickle cell anemia?

A

HbS polymerizes when deoxygenated

low O2, high altitude or acidosis precipitates sickling -> anemia and vaso-occlusive disease

41
Q

What treatment increases HbF?

A

hydroxyurea

42
Q

What are the complications of sickle cell anemia?

A

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
Q

How can sickle cell trait be diagnosed?

A

Metabisulfite screen -> causes any amount of HbS to sickle –> (+) in both disease and trait

Hb electrophoresis

44
Q

Hemoglobin C

A

AR mutation in beta chain: glutamic acid-> lysine

  • mild anemia w extravascular hemolysis
  • HbC crystals on smear
45
Q

Pyruvate kinase deficiency

A

AR. Defect in pyruvate kinase -> decrease ATP -> rigid RBCs

-hemolytic anemia in newborn

46
Q

Paroxysmal nocturnal hemoglobinuria (PNH)

A

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
Q

Glucose-6-phosphate dehydrogenase (G6PD) deficiency

A

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
Q

Immune hemolytic anemia - IgG mediated

A

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
Q

Immune hemolytic anemia - IgM mediated

A

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
Q

Diagnosis of immune hemolytic anemia

A

Direct Coombs test -> confirms presence of ab or complement-coated RBC

Indirect Coombs test -> confirms presence of abs in patient serum

51
Q

Anemia due to underproduction (non-hemolytic)

A

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
Q

Aplastic anemia

A

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
Q

Lead poisoning

A

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
Q

Acute intermittent porphyria

A

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
Q

Porphyria cutanea tarda

A

Affected enzyme: Uroporphyrinogen decarboxylase

Accumulated substrate: Uroporphyrin (tea-colored urine)

Presenting symptoms: Blistering cutaneous photosensitivity** Most common porphyria

56
Q

Leukopenia

A

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
Q

Neutrophilic leukocytosis

A

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
Q

Monocytosis

A

increased monocytes

Causes: chronic inflammatory states and malignancy

59
Q

Eosinophilia

A

increased circulating eosinophils

Causes:
allergic rxns
parasitic infections
Hodgkin lymphoma (increased IL-5 production)

60
Q

Basophilia

A

increased circulating basophils

Causes: CML (Chronic Myeloid Leukemia)

61
Q

Lymphocytic leukocytosis

A

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
Q

Infectious Mononucleosis

A

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
Q

Acute leukemia - general characteristics

A

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
Q

Acute lymphoblastic leukemia (ALL)

A

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
Q

B-ALL

A

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
Q

T-ALL

A

TdT+ lymphoblasts expressing markers ranging from CD2-8

  • Teenagers
  • Thymic (mediastinal) mass –> called Acute Lymphoblastic LymphOMA
67
Q

Acute myeloid leukemia (AML)

A

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
Q

Acute promyelocytic leukemia

A

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
Q

Acute monocytic leukemia

A

Proliferation monoblasts -> infiltrate gums

-LACK MPO

70
Q

Acute megakaryocytic leukemia

A

Proliferation of megakaryoblasts; LACK MPO

-Associated with Down syndrome, kids YOUNGER than 5 yo

71
Q

Chronic leukemia - general

A

neoplastic proliferation of MATURE circulating lymphocytes

-insidious onset and seen in older adults

72
Q

Chronic lymphocytic leukemia (CLL)

A

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
Q

Hairy cell leukemia

A

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
Q

Adult T-cell leukemia/lymphoma (ATLL)

A

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
Q

Mycosis Fungoides

A

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
Q

What are general complications that can occur in myeloproliferative disorders (MPD)

A

Complications:
Increased risk hyperuricemia and gout (high cell turnover -> increased uric acid)

Progression to marrow fibrosis or transformation to acute leukemia

77
Q

Chronic myeloid leukemia (CML)

A

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
Q

How is CML distinguished from leukemoid reaction?

A
  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
Q

Polycythemia vera

A

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
Q

How is polycythemia vera differentiated from reactive polycythemia or ectopic EPO production?

A

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
Q

Essential thrombocythemia

A

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
Q

Myelofibrosis

A

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
Q

Causes of lymphadenopathy

A

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
Q

Lymphoma: Hodgkin vs Non-Hodgkin

A

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
Q

Follicular lymphoma

A

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
Q

Mantle cell lymphoma

A

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
Q

Marginal zone lymphoma

A

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
Q

Burkitt lymphoma

A

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
Q

Diffuse large B-cell lymphoma

A

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
Q

Hodgkin lymphoma

A

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
Q

Multiple myeloma

A

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

  1. Elevated serum protein (increased Ig production)
  2. M spike on SPEP; due to monoclonal IgG or IgA
  3. Risk of infection since lack antigenic diversity -> infection is most common cause of death
  4. Rouleaux formation - piled up RBCs on smear (increased protein decreases charge btwn RBCs)
  5. Increased light chains circulating:
    - in blood-> Primary AL amyloidosis
    - in urine -> Bence Jones protein
    - in kidney -> renal damage
92
Q

Monoclonal gammopathy of undetermined significance (MGUS)

A

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
Q

Waldenstrom Macroglobulinemia

A

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
Q

Langerhans cell histiocytosis

A

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)

Heme/Onc (2 decks)

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