Hematology & Oncology

Question 1

Microcytic Anemia

Answer 1

MCV division that occurs to maintain [Hgb]

Include: Iron deficiency anemia, anemia of chronic disease, sideroblastic anemia, & thalassemia

Question 2

Iron Deficiency Anemia

Answer 2

Microcytic Anemia due to decreased Iron levels

Most common type of anemia; lack of iron is most common nutritional deficiency in the world

=Microcytic, hypochromic RBCs w/ ↑ RDW, ↑ TIBC, & ↑ FEP (free erythrocyte protoporphyrin), ↓ ferritin, ↓ serum iron, & ↓ % saturation (normal is 33%)

Tx - supplemental iron (ferrous sulfate) + treat underlying cause

Question 3

Stages of Iron Deficiency

Answer 3

1 - Storage iron is depleted = ↓ ferritin; ↑ TIBC
2 - Serum iron is depleted = ↓ serum iron; ↓ % sat
3 - Normocytic anemia - BM makes fewer, but normal-sized, RBCs
4 - Microcytic, hypochromic anemia - BM makes smaller & fewer RBCs

Question 4

Anemia of Chronic Disease

Answer 4

Microcytic Anemia associated w/ chronic inflammation (most common type of anemia in hospitalized patients),

Chronic disease results in acute phase reactants from the liver including Hepcidin

Hepcidin sequesters iron by limiting iron transfer from macrophages to erythroid precursors & suppressing EPO production (aiming to prevent bacteria from accessing iron)

= ↑ ferritin & FEP; ↓ TIBC, serum iron & % saturation

Tx - address underlying cause; Exogenous EPO useful in some Pt (esp. those w/ cancer)

Question 5

Sideroblastic Anemia

Answer 5

Microcytic Anemia due to defective protoporphyrin synthesis

Conversion of succinyl CoA to ALA by ALAS (aminolevulinic acid synthetase w/ B6 cofactor) is rate limiting step; ALAD and ferrochelatse - inhibited by Lead

Can be Congenital (ALAS defect most common) or Acquired - Alcohol (mitochondrial poison), Lead poisoning, B6 deficiency (commonly from AE of isoniazid Tx for TB)

= ↑ ferritin, serum iron and % sat; ↓ TIBC = iron overloaded state

Iron enters mitochondria & remains trapped there (as there is not protoporphyrin for it to be attache to) and Iron-laden mitochondria for a ring around the nucleus of erythroid precursors = ringed-sideroblasts

Question 6

Thalassemia

Answer 6

Microcytic Anemia due to decreased synthesis of globin chains of Hgb

Inherited mutation (carriers are protected from P. falciparum)

Question 7

α-thalassemia

Answer 7

usually due to gene deletion (normally 4 α genes present on chromosome 16)

1 gene deleted = asymptomatic
2 genes deleted = mild anemia w/ ↑ RBC count
Cis - (same chromosome) seen in asians, worse cuz ↑
risk of severe thalassemia in offspring
Trans - seen in Africans (including African Americans)
3 genes deleted = Severe anemia, HBH (β chain tetramers) damage RBCs
4 genes deleted = lethal in utero (hydrops fetalis), HB Barts (gamma chain tetramers) damage RBCs

Question 8

β-thalassemia

Answer 8

usually due to gene mutation (normally 2 β genes present on chromosome 11) - ween in indeviduals of African & Mediterranean descent

β-Thal minor (β/β+) - usually asymptomatic w/ ↑ RBC count; microcytic, hypochromic RBCs & target cells on blood smear; ↓ HbA w/ ↑ HbA2 & HbF

β-Thal major (β°/β°) - presents w/ severe anemia a few months after birth (high HbF temporarily protective)
=unpaired α chains precipitate & damage RBC membrane
Extramedullary hematopoiesis = hepatosplenomegaly + crewcut skull & chipmunk facies (due to hematopoiesis in skull and facial bones)
Smear show microcytic, hypochromic RBCs w/ target cells & nucleated RBCs; HbA2 & HbF w/ little or no HbA
Tx - chronic transfusions often necessary (leads to risk or secondary hemochromatosis)

Question 9

Macrocytic Anemia

Answer 9

MCV > 100 µm3

Most commonly due to folate or Vit B12 deficiency (necessary for synthesis of DNA precursors)

=impaired division & enlargement of RBC precursors leads to megaloblastic anemia
=impaired division of granulocytic precursors leads to hypersegmented neutrophils (>5 lobes)
=Megaloblastic change also seen in rapidly-dividing epithelial cells

Other causes of macrocytic anemia (w/out megaloblastic change) = alcoholism, liver disease & drugs (ex 5-FU)

Question 10

Folate Deficiency

Answer 10

Dietary folate is obtained from green vegetables & some fruits; absorbed in the jejunum

Causes = poor diet, increased demand (pregnancy, cancer, hemolytic anemia), & folate antagonists (ex methotrexate)

= Macrocytic RBCs & hypersegmented neutrophils
Glossitis (inflammation of tongue epithelium)
↑ serum homocysteine (↑ risk of thrombosis)
↓ serum folate
normal methylmalonic acid

Question 11

Vitamin B12 Deficiency

Answer 11

Complexed to animal-derived proteins (get from meat)
-salivary gland liberates, then binds R-binder; pancreatic proteases in duodenum detach B12 from R-binder; IF binds B12 in small bowel, & IF-B12 absorbed in ileum

Less common than folate deficiency due to large hepatic stores (takes years to develop)

Pernicious anemia most common cause (autoimmune destruction of parietal cells = IF deficiency); pancreatic insufficiency & damage to terminal ileum = other causes

= Macrocytic RBCs w/ hypersegmented neutrophils
Glossitis
↑ Serum homocysteine (↑ risk of thrombosis)
↓ serum Vitamin B12
↑ methylmalonic acid = Subacute combined
degeneration of spinal cord
(B 12 is a cofactor for the conversion of methylmalonic acid to succinyl CoA)

Question 12

Normocytic Anemia

Answer 12

Anemia w/ normal sized RBC (MCV = 80-100)

Due to ↑ peripheral destruction or underproduction

Reticulocytes (young RBCs = large cells w/ bluish cytoplasm due to residual RNA) help distinguish etiology
- Normal Retic count is 1-2%
- proper functioning BM respond to anemia by ↑ RC - >3%
- corrected RC = RC * Hct/45
>3% = good response & suggests peripheral destruction
<3% = poor BM response & suggests underproduction

Question 13

Extravascular Hemolysis

Answer 13

involves RBC destruction by the reticuloendothelial system (macrophages of the spleen, liver & lymph nodes)

= Macrophages consume RBCs and break down Hgb

Pw/ Anemia w/ splenomegaly, jaundice due to unconjugated bilirubin, ↑ risk of bili gallstones, & bone marrow hyperplasia

Labs - ↑ unconjugated bili
- Corrected RC >3%

Question 14

Intravascualr hemolysis

Answer 14

Involves destruction of RBCs w/in the blood vessels

= ↓ haptoglobin (binds Hgb in blood and takes it to spleen to be salvaged)
=hemoglobinemia -> hemoglobinuria -> hemosiderinuria (renal tubule cells pick up some of the hemoglobin that is filtered in the urine & break it down into iron, which accumulates as hemosiderin, which then ends up in the urine when the tubular cells are shed)

Question 15

Hereditary Sperocytosis

Answer 15

Normo- anemia w/ predominant extravascular hemolysis

Inherited defect of RBC cytoskeleton-membrane tethering proteins (ankyrin, spectrin, or band 3.1)
= membrane blebs for & are lost over time, as membrane is lost RBCs for spherocytes which are less able to maneuver the splenic sinusoids & are consumed by splenic macrophages => anemia

Labs - Spherocytes w/ loss of central pallor; ↑ RDW, ↑ MCHC, ↑ unconjugated bili
- splenomegaly & ↑ risk of bili gallstones

Dx- osmotic fragility test (↑ fragility in hypotonic solution)
Tx - splenectomy = anemia resolves, but spherocytes persist & Howell-Jolly bodies emerge on blood smear

Howell - Jolly bodies = fragments of nuclear material

↑ risk for aplastic crisis w/ parvovirus B19 infection

Question 16

Sickle Cell Anemia

Answer 16

Normo- anemia w/ predominant extravascular hemolysis

AR mutation of β chain (glutamic acid -> valine)
(trait = 1 mutation, disease present w/ 2 β chain mutations) (β mutation has protective role against falciparum malaria)
=HbS polymerizes when deoxygenated & polymers aggregate into needle-like structures = sickle cells

↑ risk or sickling w/ hypxemia, dehydration, & acidosis

Labs - Sickle cells & target cells on blood smear (in SCD)
- Metabisulfite screen causes cellw w/ any amount of HbS to sickle (= + in both SCT & SCD)
-HbS presence confirmed w/ electrophoresis
-Howell-Jolly bodies on blood smear
SCD = 90% HbS, 8% HbF, 2% HbA2
SCT = 55% HbA, 43% HbS, 2% HbA2

Note - from expansion of hematopoiesis & hepatomegaly from extramedullary hematopoiesis

Dactylitis = swollen hands & feet due to vaso-occlusive infarcts in bones = common presenting sign in infants (around 6 months, as [HbF] decreases)
Autosplenectomy common = ↑ risk of infection w/ encapsulated organisms (S. pneumonia, H. flu…)
↑ risk of Salmonella paratyphi osteomyelitis

Encapsulated organism infection = most common cause of death in SC children
Acute chest syndrome (from vaso-occlusion in pulmonary microcirculation) = most common cause of death in adult patients (often precipitated by pneumonia)

Question 17

Hemoglobin C

Answer 17

Normo- anemia w/ predominant Extravascular hemolysis

AR mutation in β chain of Hgb (glutamic acid -> lysine)

Pw/ mild anemia due to extravascular hemolysis

Characteristic HbC crystals in RBCs on blood smear

HbC, lyCine, Crystals

Question 18

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Answer 18

Normo- anemia w/ predominant intravascular hemolysis

Acquired defect in myeloid stem cells (= absent GPI); renders cells susceptible to destruction by complement
(normally - GPI secures DAF to RBC membrane; DAF inhibits C3 convertase = protects against complement)

= intravascular hemolysis occurs episodically, often at night (when mild respiratory acidosis develops) = hemoglobinemia & hemoglobinuria (esp in morning)
- compliment lysis RBCs, WBCs & platelets

Sucrose test used to screen; acidified serum test or flow cytometry are confirmatory tests

Main cause or death = Thrombosis of hepati, portal, or cerebral veins (destroyed platelets release cytoplasmic contents into circulation, inducing thrombosis)

Complications = iron deficiency anemia (due to chronic loss of Hgb) & AML (develops in 10%)

Question 19

G6PD (Glucose-6-phosphate dehydrogenase) Deficiency

Answer 19

Normo- anemia w/ predominant intravascular hemolysis

XR disorder = ↓ half-life of G6PD = renders cells susceptible to oxidative stress
↓ G6PD -> ↓ NADPH -> ↓ glutathione (an antioxidant) = oxidative injury by H2O2 -> intravascular hemolysis

African variant = mildly ↓ G6PD T1/2 = mild intravascular hemolysis w/ oxidative stress
Mediterranean variant = markedly ↓ G6PD T1/2 = marked intravascular hemolysis w/ oxidative stress
(high carrier frequency in both populations is likely due to protective role against falciparum malaria)

Oxidative stress precipitates Hb as Heinz bodies (can only be seen w/ a special stain - Heinz preparation), which are removed from RBCs by splenic macrophages = bite cells

Pw/ hemoglobinuria & back pain hours after exposure to oxidative stress

Oxidative stresses include infections, drugs (primaquine, sulfas & dapsone…) & fava beans

Question 20

Immune Hemolytic Anemia (IHA)

Answer 20

Normo- anemias w/ predominant Intravascular hemolysis

Ab-mediated (IgG or IgM) destruction of RBCs

IgG mediated usually involves extravascular hemolysis (binds in warm areas of body = centrally) - Ab coated RBCs consumed by splenic macrophages = spherocytes

• Associated w/ SLE, CLL, drugs (penicillin, cephalosporins, α-methyldopa)
• Tx = cessation of offending drug; steroids, IVIG, and splenectomy (if necessary)

IgM mediated usually involves intravascular hemolysis (bind RBCs & fix compliment in cold temp or extremities (cold agglutinin))
-Associated w/ Mycoplasma pneumoniae & infectious mononucleosis

Dx w/ Indirect or Direct Coombs test

Question 21

Microangiopathic Hemolytic Anemia

Answer 21

Intravascular hemolysis that results from vascular pathology; RBCs are destroyed as they pass through circulation

Occurs w /microthrombi (TTP-HUS, DIC, HELLP), prosthetic heart valves, & aortic stenosis; when present, microthrombi produce schistocytes on blood smear

Normo- anemia w/ predominant intravascular hemolsysis
- Iron deficiency anemia can occur w/ chronic hemolysis

Question 22

Malaria

Answer 22

Infection of RBCs & liver w/ Plasmodium spp. transmitted by female Anopheles mosquito

= RBCs rupture as a part of the Plasmodium life cycle, resulting in intravascular hemolysis and cyclical fever (daily w/ falciparum, every other day w/ vivax & ovale)

Spleen also consumes some infected RBCs = mild extravascular hemolysis w/ splenomegaly

= Normo- anemia w/ predominant intravascular hemolysis

Question 23

Anemia due to Underproduction

Answer 23

↓ production of RBCs by bone marrow; characterized by low corrected reticulocyte count (<3%)

Etiologies include

1) causes of micro & macrocytic anemia
2) Renal failure (↓ EPO production by peritubular interstitial cells)
3) Damage to BM precursor cells (may result in anemia or pancytopenia)

Question 24

Parvovirus B19

Answer 24

Infects progenitor RBCs & temporarily halts erytropoiesis; leads to significant anemia in the setting of preexisting marrow stress (e.x. sickle cell anemia)

Tx - supportive (infection is self-limited)

Question 25

Aplastic Anemia

Answer 25

Damage to hematopoietic stem cells, resulting in pancytopenia w/ low retic count Etiologies include drugs/chemicals, viral infections, & autoimmune damage Biopsy reveals empty & fatty marrow Tx - cessation of causative agents & supportive care w/ transfusions and marrow-stimulating factors (EPO, GM-CSF, G-CSF...) - immunosuppression may be helpful (some cases due to abnormal T-cell activation w/ cytokine release) - last resort = BM transplant

Question 26

Myelophthisic process

Answer 26

pathologic process (e.g. metastatic cancer) that replaces bone marrow = hematopoiesis is impaired = pancytopenia

Question 27

Disorders of Primary Hemostasis

Answer 27

Primary Hemostasis = Forming a platelet plug (through GPIb, GPIIb/IIIa, fibrinogen) = usually due to abnormalities in platelets Clinical features include mucosal & skin bleeding - epistaxis (most common), hemoptysis, GI bleeds, hematuria & menorrhagia; intracranial bleeds if severs - petechiae (1-2mm), purpura (>3mm), ecchymosis (>1cm) Labs - Platelet count <50 K/uL (leads to symptoms) ↑ bleeding time blood smear to asses #/size of platelets BM biopsy to assess magakaryocytes

Question 28

Immune Thrombocytopenic Purpura (ITP)

Answer 28

Quantitative platelet disorder due to autoimmune production of IgG against platelet antigen (e.x.GPIIb/IIIa - cross-links w/ fibrin) -Auto-Ab produced by plasma cells in the spleen & Ab-bound platelets are consumed by splenic macrophages Most common cause of thrombocytopenia in children & adults -Divided into acute & chronic forms Labs - ↓ platelets (often <50 K/ul), - Normal PT/PTT - ↑ megakaryocytes on BM biopsy Tx - initial = corticosteroids (adults may show early response and then relapse) - IVIG is used to raise the platelet count in symptomatic bleedint (but its effect is short lived) - Splenectomy eliminates the primary source of Ab & the site of platelet destruction

Question 29

Acute ITP

Answer 29

arises in children weeks after a viral infection or immunization Self-limited, usually resolving w/in weeks of presentation

Question 30

Chronic ITP

Answer 30

Arises in adults, usually women of child-bearing age. May be primary or secondary (e.x. SLE) IgG can cause the placenta = may cause short lived thrombocytopenia in offspring

Question 31

Microangiopathic Hamolytic Anemia

Answer 31

Quantitative platelet disorder due to pathologic formation of platelet microthrombi in small vessels - platelets are consumed in the formation of microthrombi = thrombocytopenia - RBCs are sheared as they cross microthrombi = hemolytic anemia w/ schistocytes Seen in TTP & HUS Labs - Thrombocytopenia w/ ↑ bleeding time - Normal PT/PTT - Anemia w/ schistocytes - ↑ megakaryocytes on BM biopsy = Skin & mucosal bleeding; Fever, Renal insufficiency (more w/ HUS), CNS abnormalities (more w/ TTP) Tx - involves plasmapheresis & corticosteroids (particularly in TTP)

Question 32

Thrombotic Thrombocytpenic Purpura (TTP)

Answer 32

Quantitative platelet disorder due to ↓ ADAMTS13 - normally cleaves vWF multimers into smaller monomers for degradation ↓ ADAMTS13 is usually due to an acquired auto-Ab (most commonly seen in adult females) = Large, uncleaved vWF multimers lead to abnormal platelet adhesion; resulting in microthrombi tend to be associated more with CNS manifestations

Question 33

Hemolytic Uremic Syndrome (HUS)

Answer 33

Quantitative platelet disorder due to endothelial damage by drugs or infection Classically seen in children w/ E coli O157:H7 dysentery (from exposure to under-cooked beef) = E coli verotoxin damages endothelial cells (& ADAMST13) resulting in platelet microthrombi Causes damage particularly in the kidneys

Question 34

Bernard-Soulier Syndrome

Answer 34

Qualitative platelet disorder due to a genetic GPIb deficiency = platelet adhesion is impaired GPIb on platelets binds vWF Blood smear shows mild thrombocytopenia w/ enlarged platelets

Question 35

Glanzmann thrombasthnia

Answer 35

Qualitative platelet disorder due to a genetic GPIIb/IIIa deficiency = platelet aggregation is impaired GPIIb/IIIa on platelets crosslinks w/ fibrin

Question 36

Other Qualitative Platelet disorders

Answer 36

Aspirin - irreversibly inactivates COX = lack of TXA2 impairs platelet aggregation -TXA2 released by platelets signals for aggregation Uremia - disrupts platelet functions; both adhesion & aggregation are impaired Uremia due to build up of nitrogenous waste products from poor kidney function

Question 37

Disorders of Secondary Hemostasis

Answer 37

Secondary Hemostasis = Stabilizes the weak platelet plug via the coagulation cascade Usually due to factor abnormalities Labs - PT (measures extrinsic VII & common pathway) - PTT (measures intrinsic XII, XI, IX, VIII & common) = deep tissue bleeding into muscles & joints (hamarthrosis) & rebleeding after surgical procedures

Question 38

Hemophilia A

Answer 38

Genetic VIII deficiency XR but can be de novo Pw/ deep tissue, joint & post-surgical bleeding Labs = ↑ PTT (normal PT) - ↓ FVIII - normal platelet count & bleeding time - PTT corrects in mixing study Tx - recombinant FVIII

Question 39

Hemophilia B (Christmas Disease)

Answer 39

Genetic IX deficiency Resembles Hemophilia A, except ↓ FXI (instead of FVIII) Pw/ deep tissue, joint & post-surg bleeding ↑ PTT; ↓ FXI; normal platelet count

Question 40

Coagulation Factor Inhibitor

Answer 40

Acquired Ab against a coagulation factor resulting in impaired factor function **anti-FVIII most common Clinical & Lab findings are similar to Hemophilia A PTT does NOT correct upon mixing study (mixing normal plasma w/ pt's plasma) because of presence of inhibitor in the patient's plasma

Question 41

Von Willebrand Disease

Answer 41

genetic vWF deficiency (AD most common) **most common inherited coag disorder Pw/ mild mucosal & skin bleeding (↓ vWF impairs platelet adhesion) Labs - ↑ bleeding time - ↑ PTT (normal PT) ↓ FVIII T1/2 (vWF stabilizes VIII) - Abnormal Ristocetin test (normally induces platelet agglutination by causing vWF to bind platelet GPIb) Tx - Desmopressin (ADH analog) = ↑ vWF release from Weibel-Palade bodies of endothelial cells

Question 42

Vitamin K Deficiency

Answer 42

Vit K is activated by epoxide reductase in the liver - Activated K carboxylates F II, VII, IX & X + Protein C & S - gamma carboxylation is necessary for factor function Deficiency occurs in Newborns & Long-term Abx therapy (gut bacteria synthesize Vit K) or w/ malabsorption (Vit K is fat soluble)

Question 43

Other causes of abnormal secondary hemostasis

Answer 43

Liver failure - ↓ production of coagulation factors & ↓ Vit K activation (by epoxide reductase) - followed by PT Large-volume transfusion = dilutes coagulation factors resulting in a relative deficiency

Question 44

Heparin-Induced Thrombocytopenia (HIT)

Answer 44

Platelet destruction that arises secondary to heparin therapy (heparin can form complex w/ platelet factor 4 & the body can produce Ab against these complexes) Fragments of destroyed platelets may activate remaining platelets, leads to thrombosis Must use another anticoagulant (but not warfarin as these pt have ↑ risk for skin necrosis)

Question 45

Disseminated Intravascular Coagulation (DIC)

Answer 45

Pathologic activation of the coagulation cascade = widespread microthrombi result in ischemia & infarction + consumption of platelets & factors results in bleeding (classically at IV sites & mucosal surfaces) **Almost always secondary to another disease process (obstetric complications, Sepsis, Adenocarcinoma, APL, Rattlesnake bite) Labs - ↓ platelet count, ↓ fibrinogen, ↑ PT & PTT - Microangiopathic hemolytic anemia (from partial thrombi) - ↑ D-dimer (fibrin split product) Tx - addressing the underlying cause & transfusing blood products & cryoprecipitate (contains coag factors)

Question 46

Disorders of Fibrinolysis

Answer 46

due to plasmin overactivity resulting in excessive cleavage of serum fibrinOGEN Pw/ ↑ bleeding (resembles DIC) Labs - ↑ PT/PTT, ↑ bleeding time, normal platelet count ↑ fibrinOGEN split products (not d-dimer because fibrin thrombi are absent) Causes = Radical prostatectomy (release of urokinase) & Cirrhosis of liver (↓ production of α2-antiplasmin (inactivates plasmin)) Tx - aminocaproic acid (blocks activation of plasminogen)

Question 47

Virchow Triad

Answer 47

= 3 major risk factors for thrombosis 1 - disruption of blood flow 2 - endothelial cell damage (B12 & folate, or CBS deficiency) 3 - hypercoagulable state (Protein C/S deficiency, F V Leiden, Prothrombin 20210A, ATIII deficiency, oral contraceptives)

Question 48

Vitamin B12 & Folate deficiency

Answer 48

result in mildly elevated homocysteine levels - ↓ conversion of homocysteine to methionine ↑ homocysteine levels are associated w/ increasing risk for thrombosis

Question 49

Cystathionine Beta Synthase (CBS) deficiency

Answer 49

CBS converts homocysteine to cystathionine -deficiency = homocysteine buildup & homocysteinuria Characterized by vessel thrombosis, mental retardation, lens dislocation, & long slender fingers

Question 50

Protein C or S deficiency

Answer 50

AD - ↓ negative feedback on the coagulation cascade Protein C & S normally inactivate V & VIII ↑ risk of warfarin skin necrosis -C & S have shorter T1/2 than II, VII, IX & X = initial warfarin therapy can cause a severe C or S deficiency ↑ risk of thrombosis (esp in the skin)

Question 51

Factor V Leiden

Answer 51

a mutated form of factor V that lacks the cleavage site for deactivation by protein C & S = Most common inherited cause of hypercoagulable state

Question 52

Prothrombin 20210A

Answer 52

an inherited point mutation in prothrombin that results in ↑ gene expression ↑ prothrombin results in ↑ thrombin, promoting thrombus formation

Question 53

Antithrombin (AT) III deficiency

Answer 53

↓ the protective effect of heparin-like molecules produced by the endothelium, ↑ risk for thrombus Heparin-like molecules usually activate ATIII, which inactivates thrombin and coag factors = in ATIII deficiency, PTT does not rise w/ standard heparin dosing (pharmocologic heparin works by binding & activating ATIII) Tx = high doses of heparin activate limited ATIII; coumadin is then given to maintain an anticoagulated state

Question 54

Oral Contraceptives & coagulability

Answer 54

are associated w/ a hypercoagulable state Estrogen induces increased production of coagulat↑↓ion factors, thereby increasing the risk or thrombosis

Question 55

Infectious Mononucleosis (IM)

Answer 55

EBV (CMV less commonly) infections that results in a lymphocytic leukocytosis comprised of reactive CD8+ T cells CD8+ T-cell response leads to: Generalized lymphadenopathy (in the lymph node paracortex); Splenomegaly (in the periarterial lymphatic sheath (PALS)); ↑ WBC w/ atypical lymphocytes Pw/ pharyngitis, hepatomegaly & ↑ Liver enzymes Complications - ↑ risk or splenic rupture; Rash if exposed to ampicillin; Dormancy in B cells = ↑ risk or recurrence & of B-cell lymphoma Screening w/ monspot & definitive Dx w/ serologic testing (for viral capsid antigen)

Question 56

Acute Leukemia

Answer 56

=neoplastic proliferation of blasts; defined as the accumulation of >20% blasts in BM 'acute' presentation of anemia, thrombocytopenia, or neutropenia (as blasts crowd-out normal hematopoiesis) High WBC due to ↑ blasts in blood stream (large, immature cells, often w/ punched out nucleoli)

Question 57

Acute Lymphoblastic Leukemia (ALL)

Answer 57

Neoplastic accumulation of lymphoblasts (>20%) in BM Lymphoblasts are characterized by + TdT staining Most commonly arises in children; associated w/ Down syndrome AFTER 5 yo Subclassified into B-ALL & T-ALL based on surface markers (HyperCVAD/araC + methotrexate; POMP maintenance)

Question 58

B-ALL

Answer 58

most common type of ALL TdT+ lymphoblasts w/ CD10, CD19 & CD20 t(12;21) more common in children = good prognosis t(9;22) (Philadelphia) more common in adults = poor prognosis Tx - usually responds well to chemo - requires prophylaxis to scrotum & CSF

Question 59

T-ALL

Answer 59

TdT+ lymphoblasts w/ CD2,3,4,7,8 (No CD10) Usually presents in teenagers as a mediastinal (thymic) mass (called lymphoblastic lymphoma because the malignant cells form a mass) T-all, Teenagers, Thymic mass

Question 60

Acute Myeloid Leukemia (AML)

Answer 60

Neoplastic accumulation of immature myeloid cells (>20%) in BM characterized by + MPO (in cytoplasmic staining) -crystal aggregates of MPO may be seen as AUER RODS Most commonly arises in older adults (50-60) subclassified based on cytogenetic abnormalities, lineage & surface markers (7+3 (araC + Durnorubicin) + araC) May also arise from pre-exicting dysplasia, especially w/ prior exposure to alkylating agents or radiotherapy

Question 61

Acute Promyelocytic Leukemia (APL)

Answer 61

t(15;17) = RAR (retinoic acid receptor) disruption, which blocks maturation = promyelocytes (blasts) accumulate **medical emergency due to ↑ risk of DIC (promyelocytes contain numerous primary granules) Tx - ATRA (tretinoin) = binds altered receptors & causes the blasts to mature

Question 62

Acute Monocytic Leukemia

Answer 62

Proliferation of Monoblasts **AML, but usually lack MPO Blasts characteristically infiltrate the gums = swelling

Question 63

Acute Megakaryoblastic Leukemia

Answer 63

Proliferation of Megakaryoblasts **AML, but lack MPO Associated w/ Down syndrome, Arise BEFORE 5 yo

Question 64

Chronic Leukemia

Answer 64

Neoplastic proliferation of mature circulating lymphocytes; characterized by high WBC counts Usually insidious in onset (can be asymptomatic), & seen in older adults

Question 65

Chronic Lymphocytic Leukemia (CLL)

Answer 65

Neoplastic proliferation of naive B cells that co-express CD5 & CD20 (normally on T-cells) * Most common leukemia overall ↑ lymphocytes & smudge cells on blood smear; involvement of lymph nodes leads to generalized lymphadenopathy Complications = Hypogammalobulinemia (infection = most common COD); Autoimmune hemolytic anemia; Transformation to diffuse large B-cell lymphoma (Richter transformation)

Question 66

Hairy Cell Leukemia

Answer 66

Neoplastic proliferation of mature B cells characterized by hairy cytoplasmic processes Cells TRAP+ (tartrate-resistant acid phosphatase) = splenomegaly (due to hairy cells 'trapped' in red pulp); 'dry tap' bone marrow on aspiration (due to BM fibrosis); * Lymphadenopathy usually absent* Tx - excellent response to 2-CDA (cladribine) (an adenosine deaminase inhibitor) = adenosine accumulates to toxic levels in neoplastic B cells

Question 67

Adult T-Cell Leukemia/Lymphoma (ATLL)

Answer 67

Neoplastic proliferation or mature CD4+ T-cells *Associated w/ HTLV-1; most commonly seen in Japan & Caribbean =rash (skin infiltration), generalized lymphadenopathy w/ hepatosplenomegaly, & lytic (punched-out) bone lesions w/ hypercalcemia (also seen in multiple myeloma) & bone pain

Question 68

Mycosis Fungoides

Answer 68

Neoplastic proliferation of mature CD4+ T-cells Characteristic lymphocytes w/ cerebriform nuclei (Sezary cells) are seen on blood smear - cells can spread to involve the lbood, producing Sezary syndrome =skin rash, plaques & nodules (skin proliferation); Aggregates of neoplastic cells in the epidermis are called Pautrier microabscesses

Question 69

Myeloproliferative Disorders (MPD)

Answer 69

Neoplastic proliferation of mature cells of myeloid lineage; disease of late adulthood (50-60) Results in high WBC count w/ hypercellular bone marrow (due to ↑ granulocyte count) **cells of all myeloid lineages are increased, but they are classified based on the predominant lineage Complications = ↑ risk of hyperuricemia & gout (due to high cell turnover = ↑ purine degredation); Progression to marrow fibrosis (burnt out phase), or transformation to acute leukemia

Question 70

Chronic Myeloid Leukemia

Answer 70

Neoplastic proliferation of mature myeloid cells, especially granulocytes & their precursors; characteristically ↑ basophils (basophilia) t (9;22) Ph+ = BCR-ABL = ↑ tyrosine kinase activity Chronic phase = enlarged spleen Accelerate phase = enlarging spleen (shows progression) Transformation to AL (2/3 AML; 1/3 ALL) Tx - Imatinib (blocks tyrosine kinase) = 1st line DDx: CML = LAP -; Basophilia; t(9;22) Ph+ Leukemoid reaction = LAP+; normal basophils & Ph- LAP (Leukocyte Alkaline Phosphatase)

Question 71

Polycythemia Vera (PV)

Answer 71

Neoplastic proliferation of mature myeloid cells, **RBCs** Associated w/ JAK2 kinase mutation Hyperviscosity of blood = blurry vision & headaches; ↑ risk of venous thrombosis (including Budd-Chiari syndrome); Flushed face; Itching (esp after bath = Aquagenic pruritis) Tx - phlebotomy (Hydroxyurea = second line) DDx: PV - ↓ EPO; normal SaO2; Reactive polycythemia - ↑ EPO & low-normal SaO2

Question 72

Budd-Chiari Syndrome

Answer 72

Thrombosis in the hepatic vein = classical triad of: Abdominal pain, ascites, hepatomegaly Polycythemia Vera is the most common cause

Question 73

Essential Thrombocythemia (ET)

Answer 73

Neoplastic prolif of mature myeloid cells **platelets** Associated w/ JAK2 kinase mutation ↑ risk of bleeding &/or thrombosis (platelets either over functioning, or not functioning) (rarely progress to marrow fibrosis or AL, & no significant risk for hyperuricemia/gout (platelets don't have DNA))

Question 74

Myelofibrosis

Answer 74

Neoplastic proliferation of mature myeloid cells **megakaryocytes** Associated w/ JAK2 kinase mutation (50%) Megakaryocytes produce excess PDGF = marrow fibrosis =Splenomegaly due to extramedullary hematopoiesis; =↑ risk or infection, thrombosis & bleeding (extramedullary hematopoiesis is not sufficient) Leukoerythroblastic smear = shows Tear-drop RBCs, nucleated RBCs & immature granulocytes

Question 75

Lymphadenopathy (LAD)

Answer 75

Enlarged Lymph Nodes - Painful LAD usually seen when draining a region of cute infection (acute lymphadenitis) - Painless LAD seen w/ chronic inflammation (chronic lymphadenitis), metastatic cancer, or lymphoma In inflammation, lymph node enlargement is due to hyperplasia of particular regions of the lymph node 1) Follicular (cortex) hyperplasia (B-cell) - in RA & early stages of HIV (for ex) 2) Paracortex hyperplasia (T-cell) w/ viral infection (ex IM) 3) Hyperplasia of sinus histiocytes is seen in lymph nodes that are draining a tissue w/ cancer

Question 76

Lymphoma

Answer 76

Neoplastic proliferation of lymphoid cells that forms a mass; may arise in a lymph node or extranodal tissue Divided into non-Hodgkin lymphoma (60%), and Hodgkin lymphoma (40%) NHL further classified based on cell type (B/T), size, pattern of growth, expression of surface markers, & cytogenetic translocations

Question 77

Follicular Lymphoma

Answer 77

(NHL) Neoplastic proliferation of small B cells (CD20+) that form follicle-like nodules t(14;18) = overexpression of BCL2 (inhibits apoptosis) Pw/ painless lymphadenopathy in late adulthood Tx- low-dose chemo & rituximab (anti-CD20 Ab) in symptomatic pt Progression to diffuse large B-cell lymphoma is an important complication - Pw/ enlarging lymph node BCL2; CD10, CD19, CD20

Question 78

Mantle Cell Lymphoma

Answer 78

Neoplastic proliferation of small B cells (CD20+) that expands the mantle zone t(11;14) = overexpression of Cyclin D (promotes G1/S transition) Pw/ painless lymphadenopthy in late adulthood Cyclin D; CD5, CD19, CD20

Question 79

Marginal Zone Lymphoma

Answer 79

Neoplastic proliferation of small B cells (CD20+) that expands the marginal zone Associated w/ chronic inflammatory states such as Hashimoto thyroiditis, Sjogren syndrome, & H pylori gastritis -marginal zone formed by post-germinal center B cells MALToma = marginal zone lymphoma in a mucosal site - Gastric MALT most common (~80%), highly associated w/ H. pylori infection & may regress w/ H. pylori Tx

Question 80

Burkitt Lymphoma

Answer 80

Neoplastic proliferation of intermediate-sized B cells (CD20+) t(8;14) = overexpression of c-myc oncogene promotes cell growth Associated w/ EBV - Classically Pw/ extranodal mass in a child or young adult - African form usually involves the jaw - Sporadic form usually involves the abdomen Characterized by high mitotic index & 'starry-sky' appearance (tingible body macrophages) on microscopy c-myc, 'starry sky', CD10, 19, 20

Question 81

Diffuse Large B-Cell Lymphoma

Answer 81

Neoplastic proliferation of large B-cells (CD20+) that fow diffusely in sheets **Most common form of NHL poorly differentiated = clinically aggressive -arises sporadically or from transformation of a low-grade lymphoma Pw/ an enlarging lymph node or an extranodal mass in late adulthood

Question 82

Non-Hodgkin Lymphoma (NHL)

Answer 82

Neoplastic proliferation of Lymphoid cells 60% of lymphomas 85% B-cell; 15% T-cell prior chemo/radiation therapy is the most common etiology clinically painless lymphadenopathy; usually arises in late adulthood

Question 83

Hodgkin Lymphoma (HL)

Answer 83

Neoplastic proliferation of Reed-Sternberg cells (large B cells w/ mutlilobed nuclei & prominent nucleoli) Classically positive for CD15 & CD30 (no CD20) RS cells secrete cytokines: - can result in B symptoms (fever, chills, WL & night sweats) - Attract Reactive lymphocytes, plasma cells, macrophages & eosinophils - May lead to fibrosis Reactive inflammatory cells make up a bulk of the tumor & form the basis for classification of HL. subtypes: Nodular sclerosis, Lymphocyte-rich, Mixed cellularity, Lymphocyte-depleted Reed-Sternburg (owl-eyed) cells, CD15, CD30

Question 84

Nodular Sclerosis HL

Answer 84

Most common subtype of HL (70%) Pw/ enlarging cervical or mediastinal lymph node in young adult, usually female Lymph node is divided by bands of sclerosis (fibrosis) * RS cells are present in lake-like spaces (lacunar cells)

Question 85

Lymphocyte rich HL

Answer 85

Best prognosis of all HL types

Question 86

Mixed cellularity HL

Answer 86

often associated w/ abundant eosinophils (RS cells produce IL-5)

Question 87

Lymphocyte-depleted HL

Answer 87

Most aggressive HL type (worst prognosis) Usually seen in the elderly and HIV+

Question 88

Multiple Myeloma

Answer 88

Malignant proliferation of plasma cells in BM *Most common primary malignancy of bone (metastatic cancer is most common overall) High serum IL-6 may be present (stims plasma cell growth and immunoglobulin production) =Bone pain w/ hypercalcemia (also ATLL) = lytic 'punched-out' lesions on X-ray =↑ serum protein = M-spike present on SPEP =↑ risk or infection (lose antigenic diversity) = Rouleaux formation of RBC on smear (RBC pile up) = Primary AL amyloidosis - Free light chains circulate in serum & deposit in tissues =Proteinuria - Free light chain is excreted in urine as Bence Jones Protein; deposition in kidney tubules leads to risk for renal failure (myeloma kidney) Hypercalcemia & bone pain w/ M-spike

Question 89

Monoclonal Gammopathy or Undetermined Significance (MGUS)

Answer 89

↑ serum protein w/ M spike on SPEP, but other features of MM are absent Common in elderly (5% of 70 yo); *1% of Pt w/ MGUS develop Multiple Myeloma each year

Question 90

Waldenstrom Macroglobulinemia

Answer 90

B-cell lymphoma w/ monoclonal IgM production = Generalized lymphadenopathy, ↑ serum protein w/ M-spike (of IgM); visual & neurologic deficits (IgM causes hyperviscosity); Bleeding Tx - plasmapheresis in acute complications (removes IgM from serum)

Question 91

Letterer-Siwe Disease

Answer 91

Malignant proliferation of Langerhans cells Pw/ skin rash & cystic skeletal defects in an infant (<2) Multiple organs may be involved = rapidly fatal

Question 92

Eosinophilic Granuloma

Answer 92

Benign proliferation of Langerhans cells in bone Pw/ pathologic fracture in an adolescent; skin is not involved Biopsy shows Langerhans cells w/ mixed inflammatory cells, including numerous eosinophils

Question 93

Hand-Schuller-Christian Disease

Answer 93

Malignant proliferation of Langerhans cells Pw/ scalp rash, lytic skull defects, diabetes insipidus, & exophthalmos in a child

Question 94

T-lymphoblastic leukemia/lymphoma

Answer 94

Immature T cell malignancy Pw/ 15% leukemia, 85% mediastinal mass (=SOB) TdT+, CD1a, CD34 & cytoplasmic CD3

Question 95

Anaplastic Large Cell Lymphoma

Answer 95

Immature T cell malignancy EMA+, "hallmark cells" CD2, 4, 5 & 30 ALK-1 + = better prognosis (and younger) ALK-1 - = worse prognosis (older)