Advanced Topics Los

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4 Most commonly transufed blood components

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1) Red blood cells –-Leukocyte-reduced:
• contain approximately 20-100 ml of residual plasma
• < 5.0 X 106 leukocytes per unit
• Volume 300-400 ml
• Hematocrit 55-65%
• 42 day shelf life (AS units)
2) Platelets--Apheresis, leukocyte-reduced: 5 day half life by two day quarantine
• Volume 100-500 ml
• > 3.0 X 1011 platelets per unit
• < 5.0 X 106 leukocytes per unit
3) Plasma frozen within 24 hours of collection (FP24)
• Prepared from whole blood collection
• Placed at < -18 C within 24 hours of collection
• Volume 200-250 ml
• Coagulation factors may be lower than those of fresh frozen plasma (FFP)
4) Cryoprecipitate- used for ex) in vol overloaded patient to give fibrinogen without too much more volume. 1 plasma = 2 cryos. Has fibrinogen, vWF, Factor 13
• Volume 5-20 ml per unit
• Single units or pre-pooled 5 units per pool.

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Infectious diseases screened for in the community blood supply

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- Hep B (1: 220K)
- Hep C (1: 1.1mil)
- HIV 1/2 (1: 2.3 mil)
- HTLV I/II (1: 2.99 mil)
- Syphilis
- CMV (tested by special order)
- West Nile virus
- Chagas disease
- Plasmodium (1: 4mil)
- Dengue fever

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6 major adverse reactions assoc with blood transfusion

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- Febrile, nonhemolytic
- Allergic
- Anaphylactoid/anaphylactic
- Acute hemolytic
- Transfusion related acute lung injury
- Transfusion associated circulatory overload

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Anemia classifications

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Two ways to think about it. Pathophysiological vs. Lab
Pathophys:
1) Inc. destruction
2) Decreased production
3) Blood loss
4) Acute vs. chronic

Lab:
Macro, normo, microcytic. and RDW.

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Red Cell indices

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Red Blood Cell (RBC) count x 10^6/mL
• Hemoglobin (Hb) g/dL
• Hematocrit (Hct) % – Ratio of the volume of erythrocytes to the volume of whole blood
Mean cell volume (MCV) fL: Average vol of RBCs
• Mean cell hemoglobin: Hb content of average cell
• Mean cell hemoglobin concentration %: avg concentration of Hb in a given volume of packed red cells
• RBC distribution width (RDW) %: amount of variation in RBC size

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Clinical findings common to all anemias

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• Skin and mucus membranes
– Pallor, scleral icterus, smooth tongue, petechiae, ulcers
• Lymphadenopathy
• Heart
– Tachycardia, cardiac dilatation, murmurs
• Organomegaly
– Splenomegaly, hepatosplenomegaly with ascites
• Central nervous system

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Findings with hemolysis - Overall features, clinical, lab

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Accelerated red cell destruction, shorten lifespan
<120 days
• Accumulation of Hb degradation products due to red
cell hemolysis
• Secondary elevation of erythropoiten due to
tissue hypoxia --> Increase red cell production by the bone marrow
Clinica:
Pallor, fatigue, tachycardia
Jaundice and scleral icterus (>3)
Gallstones (chronic hemolysis)
Dark-colored or pink-colored urine
Evidence of extramedullary hematopoiesis (chronic)
Expansion of bone marrow and thinning of cortical bone --> Skeletal abnormalities (mostly in kids)
Splenomegaly, Hepatomegaly
Presence and severity depends on pathophys of the hemolysis

Lab:
• Reticulocytosis
• Spherocytes and or schistocytes
• Bone marrow erythroid hyperplasia
• Hyperbilirubinemia
• Hemoglobinemia
• inc Serum lactate dehydrogenase (LDH)

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Hereditary spherocytosis

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Epi: people of European descent, 1 in 5000
65% dominant
Pathophys: mutations in the ankyrin gene are most common, but
defects of band 3 and alpha spectrin are also seen. These mutations cause a defective network to be formed, which makes the RBC membrane less deformable, leading to surface blebs and changes in
RBC shape. Less flexibility makes it hard for the RBC to pass through small channels. Getting caught in splenic sinusoids leads to phagocytosis by splenic macrophages.
Clinical presentation: all of the classic changes of chronic hemolytic anemia, including the crises, variable severity (from obvious hemolysis at birth to asymptomatic)
Gross: findings: enlarged spleen (500-1000g)
Micro: circulating spherocytes (small, no
central pallor), reticulocytosis, splenic congestion,
hemosiderosis, and increased erythropoiesis in the marrow
Diagnosis: history, osmotic fragility test

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Glucose-6-Phosphate Dehydrogenase deficiency

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Epi: variants in African, Mediterranean, or Middle Eastern descent, all are X-linked! Affected women are heterozygous and therefore have (dimorphic) populations of RBCs/variable presentation (lyonization)
Lack of G6PD is protective against Plasmodium falciparum infection. Mutations either
lead to decreased synthesis of G6PD, but more commonly prod. of enzyme that is unstable and more easily broken down. (The level of the enzyme will be normal in retics, but diminishes as the RBC ages.)
Clinical: Classified (four classes) by the severity of the
enzyme deficiency (class I is most severe); patients present with hemolysis after an “oxidative stress” such as infection (leukocytes generate free radicals--viral hepatitis, pneumonia, typhoid fever) or consumption of an oxidizing food (fava beans) or drug (primaquine,
chloroquine, sulfonamides, nitrofurantoins); chronic hemolytic anemia, but with an intermittent pattern, so signs/symptoms are less severe.
Anatomic (gross) findings: None
Micro: Heinz bodies, bite cells, spherocytes; reticulocytes (during recovery)
Diagnosis: fluorescent spot or ascorbate cyanide (screening tests); quantitative assay

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Sickle cell disease

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Epi: 8% of African Americans are heterozygous for Hb S = Sickle cell trait
Pathophys: Many possible mutations can occur in the β globin gene, the most common clinically significant mutation is the one that causes sickle cell disease (point mutation, substitutes valine for glutamine).
Causes the hemoglobin to polymerize and crystallize
when under oxidative stress. Survival advantage of
being resistant to Plasmodium falciparum infection. The sickle shape can initially be reversed with re-oxygenation, but with repeated cycles of sickling, the damage becomes irreversible. This leads to secondary membrane damage, inflexibility, and hemolysis.
Clinical presentation: Sickle cell trait (heterozygous HbS and HbA) rarely causes sickling, except under severe conditions. Sickle cell anemia (homozygous HbS) will sickle and hemolyze under low stress
conditions. Sickled cells are rigid and get stuck in the splenic sinusoids also in small vessels of organs. It is possible to be a double heterozygote, e.g. HbC can also form tetramers with HbS; patients with SC Disease have fewer problems than those with
SS Disease. During the first six months of life homozygotes still make fetal hemoglobin (α2γ2) instead of beta globin (α2β2), so sickling is not seen until the fetal hemoglobin levels decline. Intracellular factors that affect the MCHC will affect the severity of the disease (e.g. dehydration makes it worse). Acidosis
(often seen with hypoxia) will also increase the tendency to sickle. These patients have all of the findings of the chronic hemolytic anemias.
They are also more susceptible to infections (loss of splenic function; defective complement opsonization).
- Painful crisis = vaso-occlusive crisis in bones (hand-foot syndrome or leg ulcers), lungs (acute chest syndrome), penis (priapism), brain (seizure or
stroke), liver or spleen (infarct)
- Aplastic crisis = sudden stop of marrow RBC production (Parvovirus)
- Sequestration crisis = sudden accumulation of RBCs in the spleen due to sludging
- Anatomic (gross) findings: initial splenomegaly with later autosplenectomy, microinfarcts accumulate into gross infarcts, especially in solid organs (liver, brain, kidneys), but also in the lungs (cor pulmonale); bone marrow expansion with thinning of cortical bone
(“crew cut” or “hair-on-end” appearance of skull x-rays)
Micro: anisocytosis, poikilocytosis, sickled cells,
reticulocytes; extramedullary hematopoiesis; infarcts
Diagnosis: clinical findings, peripheral smear with sickle cells; Sickledex, hgb electrophoresis; prenatal DNA testing for affected fetus

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Lab manifestations of autoimmune hemolytic anemia,

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Coombs’ antiglobulin test = direct antiglobulin test (DAT) = Coombs test
Detects the presence of antibodies on the surface of RBCs. The antibodies are detected by reagent anti-human antibodies that attach to the Fc end of human
antibodies = anti-human globulin (AHG). The antibodies can have variable clinical significance—some only sit on the RBC surface without causing damage, others cause rapid life-threatening hemolysis.

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Warm AIHA

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Warm Antibody ImmunoHemolytic Anemia = Warm AutoImmune Hemolytic Anemia
(WAIHA) The most common form of AIHA; half are idiopathic, half are secondary (leukemia, other autoimmune conditions, other neoplasms, drug-induced); by definition,
the autoantibody must be active at 37 C (body temperature)
Pathophys: Antibodies are sometimes made that are directed against non-foreign (“self”) antigens. Warm-reacting autoantibodies are often
IgG, rarely IgA, that coat the RBC surfaces. The antibodies usually have no defined specificity, but sometimes are directed against Rh
antigens. Their Fc ends (and the RBC membrane they are attached to) get caught by monocytes/macrophages, leading to spherocyte
formation. The spleen then clears the spherocytes.
- Clinical presentation: extravascular hemolysis, anemia (pallor, weakness, fatigue, malaise), and history of a condition that might
be associated with secondary WAIHA
- Anatomic (gross) findings: splenomegaly
- Micro: spherocytes, reticulocytes
- Diagnosis: clinical presentation, CBC, DAT

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Cold AIHA

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These are typically IgM antibodies; by definition, they do not react at 37 C; they are usually most active at 0-4 C, but some can maintain activity up to 32 C. They
do not typically cause clinically significant (severe) hemolysis, but chronic lowgrade hemolysis.
Assoc. mycoplasma, C. perfringens (I think)
Pathophys: IgM molecules are pentamers and more capable of causing RBCs to clump together (agglutinate). They typically cause
RBC destruction by activating complement on the RBC surface (lysis). The C3b fragments on the surface lead to phagocytosis by monocytes/macrophages.
- Clinical presentation: Positive DAT or agglutination on peripheral blood
smears during recovery from mycoplasma pneumonia or infectious mononucleosis; if hemolysis is present, it is usually self-limited. The positive
DAT might be seen chronically as an idiopathic condition or in association with lymphoproliferative disorders. Patients might present with Raynaud phenomenon or pallor and cyanosis of the extremities due to vascular obstruction.
 Anatomic (gross) findings: None
 Microscopic findings: spherocytes, reticulocytes, RBC agglutination
 Diagnosis: clinical presentation,CBC (with peripheral smear), DAT

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Mechanical hemolysis and assoc. clinical conditions

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Damage is most common with intravascular
prostheses such as mechanical heart valves, ECMO, cardio-pulmonary bypass, ventricular assist devices, or vascular grafts (at the suture line). It is also
typically seen in inflammatory conditions that allow fibrin to deposit within small vessels. The resulting partial occlusion by the fibrin strands pinches off pieces of the RBC membrane (microangiopathic hemolytic anemia). Examples include
disseminated intravascular coagulation (DIC), malignant hypertension, SLE, and thrombotic thrombocytopenic purpura/hemolytic
uremic syndrome (TTP/HUS).
Clinical presentation: history as described above plus evidence of hemolysis
 Anatomic (gross) findings: None
 Microscopic findings: fragmented red cells (helmet cells, triangle cells, other non-specific schistocytes)

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Alpha thalassemia

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Chr 16. most commonly in people of the Mediterranean, Africa, and Southeast Asia
- Gene deletion of one or more of the 4 genes

Silent carrier 3: -a/aa Normal
Thalassemia trait 2: -a/-a or --/aa Mild microcytic anemia
HgH disease 1: -a/-- Hemolytic anemia
Hb Bart’s disease 0: --/-- Severe anemia, stillborn

Treatment: transfusion, iron chelators; hematopoietic stem cell transplant for severe cases
Clinical presentation/anatomic findings: varies from asymptomatic to growth
retardation in severely affected children; fatigue from severe anemia;
hepatosplenomegaly and enlarged bony prominences from extramedullary
hematopoiesis- “frontal bossing” (due to enlargement of facial bones); bone
marrow expansion (“crew cut: or “hair-on-end” appearance of skull x-rays)
Microscopic findings: hypochromic, microcytic anemia; decreased MCHC;
anisocytosis; target cells; basophilic stippling; schistocytes; reticulocytes;
circulating nucleated RBCS (nRBCs)
Diagnosis: clinical presentation, family history, CBC, hemoglobin electrophoresis;
DNA analysis

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Beta thalassemia all overview

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Two b genes: impaired, absent, deleted gene. Mediterranean descent
Beta thalassemia major
– β0β0 or β+β+ which causes Severe anemia; massive hepataosplenomegaly; bony deformity. Requires chronic blood transfusion
– Hemoglobin electrophoresis: elevated HbF (30-100%)
• Thalassemia intermedia
– β+β+ OR β+β0
• Beta thalassemia trait
– ββ0
– Mild microcytic anemia with elevated or normal RBC count
– Hemoglobin electrophoresis: elevated HbA2

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Beta thalassemia major lab findings

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• Severe anemia
– Hgb 3-6 g/dL
• Laboratory findings:
• Microcytic, hypochromic anemia
• Target cells, basophilic stippling, schistocytes
• Reticulocyte count not as elevated as should be for the degree of anemia
• Nucleated RBCs
• Hb F markedly increased (α2 γ2)
• Hb A2 normal, low, or high

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Hgb H disease

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a tetramer of β globin causing transfusion-dependent anemia, bone marrow expansion, as it has an extremely high affinity for oxygen and is unstable, forming precipitates which causes splenic removal of RBCs (seen in southeast Asian population)

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Drug-induced hemolysis

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Hapten model – typically seen after IV drug administration, 1-2 weeks after
therapy is initiated.
The drug attaches to the RBC surface; antibodies are generated that are directed
either against the drug alone (penicillin, cephalosporins) or the drug + RBC
membrane (quinidine), leading to either intra- or extravascular hemolysis.Anemias - 8
Autoantibody model – antibodies are generated that are directed against the
RBC membrane (e.g. Rh antigens), but not the drug (α-methyldopa). This type is
less likely to be clinically significant (10% might have antibodies, but only 1%
have any evidence of hemolysis). Except for drug-associated history, findings will
be the same as for WAIHA.

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Megaloblastic anemia overview

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Impaired DNA synthesis: RBCs and their precursors are abnormally large (due to abnormal cell maturation and division); folate and vitamin B12 are both coenzymes involved in the DNA synthetic pathway, so deficiency of either can cause megaloblastic change (RNA and protein functions are not affected, so cytoplasm appears normal)
Microscopic findings: anisocytosis, normochromia, macroovalocytes (MCV > 100fL), relatively few reticulocytes; occasional circulating nRBCs;
neutrophils are large and hypersegmented (macropolymorphonuclear);
bone marrow is hypercellular with megaloblastic changes, mature RBC precursors have appropriate cytoplasm, but retain immature-looking nuclei (nuclear-cytoplasmic asynchrony); similar changes are seen in the myeloid and megakaryocytic lineages. Myeloid:Erythroid ratio (normally 3:1) is closer to 1:1. These abnormal precursors lead to ineffective erythropoiesis; their progeny are less stable than normal RBCs so they hemolyze.

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Causes of B12 deficiency

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Inadequate amounts in the diet (vegetarians)
 Achlorhydria/pepsin deficiency (elderly people)
 Lack of IF (gastrectomy, pernicious anemia)
 Exocrine pancreas deficiency (pancreatitis)
 Ileal disease or surgical resection
 Relative deficiency in spite of normal absorbing ability (tapeworms,
pregnancy, hyperthyroidism, cancer)

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Pernicious anemia

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- 5th to 8th decades, most common inScandinavians and UK populations, probable genetic predisposition to form autoantibodies; relatively higher incidence of gastric cancer
- Clinical presentation: Insidious onset of symptoms of anemia, leukopenia, thrombocytopenia, achlorhydria, and spastic paraparesis with sensory ataxia and paresthesias of the legs (subacute combined degeneration of the spinal cord or combined severe disease)
- The underlying problem is chronic atrophic gastritis: immune-mediated (probably an autoimmune T-cell response) destruction of the gastric mucosa, loss of the IF-secreting parietal cells. This leads to a drop in
B12 stores and causes the anemia and associated findings.
 Three types of associated antibodies:
 - Type I (seen in 75% of cases) = blocking antibody: blocks binding of B12 and IF (present in serum and gastric fluid)
- Type II: prevents binding of IF or IF-B12 complex to ileal receptors
 -Type III (seen in 85-90% of cases, but nonspecific) = parietal canalicular antibody: directed against the gastric proton pump found in the microvilli
of parietal cells; more likely to be a response to gastric damage than a cause of it.
 Anatomic (gross) findings: atrophic glossitis (shiny, “beefy” red tongue);
diffuse chronic gastritis; spinal cord atrophy of the dorsal and lateral tracts (75% of cases)
 Microscopic findings: atrophy of fundic glands (loss of both chief andparietal cells); replacement by mucus-secreting (goblet) cells
(intestinalization or intestinal metaplasia); enlargement of cells and nuclei (megaloblastic change); infiltration by lymphocytes and plasma cells;
spinal cord myelin degeneration in the dorsal and lateral tracts; ganglia degeneration in posterior nerve roots and peripheral nerves
 Diagnosis: low serum B12 levels; high serum and urinary methylmalonic acid; Schilling test – inability to absorb radiolabelled oral cobalamin
(measure by excretion of cyanocobalamin in the urine); dramatic reticulocytosis in response to parenteral B12; measure antibodies to IF

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Iron deficiency anemia

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Probably the most common nutritional deficiency in the world (including the US). Highest risk populations: toddlers, adolescentgirls, and women of childbearing age.
Causes of Iron Deficiency
 Insufficient dietary intake (infants, vegetarians, elderly)
 Impaired absorption (intestinal disease, gastrectomy, diets rich in tannates, CO3s, PO4s)
 Increased requirement (pregnancy, children during growth spurts)
 Chronic blood loss (peptic ulcers, GI cancer, hematuria, menorrhagia, GYN cancers)
 Laboratory: Usually insidious onset; findings of anemia, possible findings of intestinal malabsorption (diarrhea); low hgb/hct; low serum iron; low transferrin saturation (<15%); high total iron binding capacity (TIBC), reflecting increased production of transferrin; low serum ferritin; high free erythrocyte protoporphyrin (reflects reduced heme synthesis); symptoms due to the cause of blood loss (GI upset, menometrorrhagia)
 Anatomic (gross) findings: koilonychia, alopecia, atrophic glossitis, atrophic gastritis, esophageal webs
 Microscopic findings: hypochromic, microcytic anemia; poikilocytosis; increased erythropoiesis (relative erythroid hyperplasia) in response to blood loss until the iron runs out (special stains for iron will then be negative)

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Anemia of chronic disease

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 Decreased red cell production (low erythropoietin levels due to
increased levels of IL-1, TNF-α, and interferon-γ seen in certain
disease states) and impaired iron transport; probably due to a defect
in the ability to release iron from the storage pool ( hepcidin)
 Very commonly seen in hospitalized patients
 May mimic iron deficiency anemia
 Underlying diseases are usually:
 Chronic infections (osteomyelitis, bacterial endocarditis, lung
abscess)
 Chronic immune disorders (rheumatoid arthritis, lupus)
 Neoplasms (lymphomas, carcinomas)
 Clinical presentation: (other than symptoms from the underlying
disease) low serum iron, low TIBC, abundant iron stores
 Microscopic findings: normocytic, normochromic or microcytic,
hypochromic anemia (usually mild)
 Treatment: treat the underlying disease; give recombinant
erythropoietin

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Causes of bone marrow failure

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Most cases (65%) are idiopathic
There are many probable mechanisms (for the idiopathic cases), but they are
placed in two main categories: 1) immunologically mediated bone marrow
suppression (T-cells reacting to antigenically altered stem cells) and 2) stem cell
defects (leading to descendant cells with poor proliferative capacity)
Sometimes, the condition is created on purpose to treat hematopoietic
malignancies (use of total body irradiation and myelotoxins such as
vincristine, busulfan, 6-mercaptopurine) with subsequent stem cell
rescue
 Other causes:
 viral infections (HIV, non ABC hepatitis)
 idiosyncratic drug reactions (chloramphenicol, streptomycin)
 pesticide exposure
 nuclear war
 radiation accidents
 Fanconi’s anemia (inherited disorder that results in decreased ability to repair DNA defects)

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Myelodysplastic Syndromes

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These disorders may occur de novo or after exposure to chemotherapy and/or radiation.
Clinical Features: The risk of developing MDS increases with age (mean age 70 years); rare in
children. Many patients are discovered incidentally on routine CBC. Others present with symptoms from anemia; less commonly, infection or easy
bruising/bleeding leads to a hematologic work-up
CBC results: Anemia is almost always present (usually normocytic or macrocytic). Low retic count. Neutropenia and thrombocytopenia less common; rare without anemia
 De novo MDS is classified into 5 categories based on the following:
 Number of cytopenias
 Number of lineages showing dysplasia in bone marrow
 Percentage of myeloblasts in bone marrow and peripheral blood
 Percentage of ringed sideroblasts
Morphology:
 The bone marrow is typically hypercellular and the following changes may be
seen:
 Erythroid cells: ringed sideroblasts (RBC precursors with iron in
mitochondria), nuclear budding (see image 1), megaloblastoid maturation
(mismatch in nuclear and cytoplasmic maturation) and multinucleation.
 Neutrophils: decreased granules (image 2) and decreased nuclear
segmentation (Pseudo-Pelger Huet change)
 Megakaryocytes: Small, decreased nuclear lobes (see image 3) or
separate nuclear lobes
 Myeloblasts may be increased, but are by definition <20%
Genetics:
 Characterized by deletions and monosomies
 Monosomies 5 and 7
 Deletions of 5q, 7q and 20q
 Translocations are exceedingly rare

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Chronic Myelogenous Leukemia

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Clinical Features:
 Incidence: 1-2 cases/100,000/year; median age at diagnosis is 5th-6th decade
 Approximately 20-40% of patients are asymptomatic at diagnosis
 Common findings: fatigue, weight loss, night sweats, abdominal fullness
 CBC results:
 Leukocytosis, typically above 50,000/uL
 Neutrophilia with left shift; Basophilia and eosinophilia are common
 Platelet count variable; from NL to elevated. Thrombocytopenia is uncommon
 Myeloblasts are not increased (in early phase of disease)
 Consider causes of reactive leukocytosis and thrombocytosis and rule out
 Three phases of the disease are described:
 In the absence of curative therapy, most patients progress from an initial chronic phase to an accelerated phase or directly to the blast phase
 Because the defect in CML lies within a pluripotent stem cell, the blast phase can be myeloid (70%) or lymphoid (30%). These phases are based on numerous criteria including (if any present):
1) Persistent increase in WBC count, spleen size, and/or platelet
count unresponsive to therapy
2) Increased myeloblasts in blood or marrow
3) Cytogenetic evolution
Morphology: The bone marrow is markedly hypercellular due to proliferation of:
 Maturing granulocyte precursors
 Megakaryocytes
 The spleen is markedly enlarged due to extramedullary hematopoiesis
 The peripheral blood shows an increase in morphologically NORMAL WBCs and
platelets, as described previously
Genetics:
 Characterized by t(9;22)(q34;q11) that results in a Philadelphia chromosome. Fuses sequences of BCR gene on chromosome 22 with regions of the
ABL1 proto-oncogene on chromosome 9 FIRST AID
 BCR-ABL1 fusion protein has enhanced tyrosine kinase activity resulting in constitutive activation of several signal transduction pathways. Deregulated proliferation, reduced adherence to stroma and
defective apoptotic response to mutagenic stimuli
HSCT: transplant indicated for patients who fail imatinib. Or for patients in accelerated or blastic phase. Allo transplant can results in 85% disease free survival if transplanted in chronic phase.

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Polycythemia Vera

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Characterized by increased RBC production that is independent of the mechanisms that normally regulate erythropoiesis. 2% evolve to AML
Clinical Features: median age at diagnosis is 60 yrs
 Three phases of disease are described:
1) Prodromal, prepolycythemic phase - borderline to only mild erythrocytosis
2) Overt polycythemic phase - significantly increased RBC mass
3) Spent phase (post-polycythemic myelofibrosis); 15-25% of patients
Px: The major symptoms are due to hypertension or vascular abnormalities related to the increased red cell mass. Headache, dizziness, visual disturbances, and paresthesias are common. Plethora and splenomegaly. 20% of patients will experience arterial or venous thrombosis; may be the first manifestation of PV. Mesenteric, portal or splenic vein thrombosis and the Budd-Chiari syndrome should always lead to consideration of PV as an underlying cause. May precede the onset of an overt polycythemic phase
 Lab results:
Pre-Polycythemic and overt polycythemia phases show Mild to overt excess of normochromic, normocytic RBCs
 Diagnostic criteria:
 Male: Hgb > 18.5 g/dL
 Female: Hgb >16.5 g/dL
 Thrombocytosis may be prominent
 Neutrophilia and rarely basophilia
 Serum erythropoietin level below normal
“Spent Phase"" Hemoglobin normalizes and then decreases. Cytopenias
Morphology:
Pre-Polycythemic and overt polycythemia
 The marrow is hypercellular due to proliferation of Erythroid precursors, Megakaryocytes. The peripheral blood shows an increase in morphologically normal RBCs, WBCs (may be left-shifted), and platelets.
“Spent Phase” - Peripheral blood shows Leukoerythroblastic reaction
 Nucleated RBCs and left-shifted granulocytes
 Tear-drop shaped RBCs
 Bone marrow
 Hypocellular marrow (Decreased RBC and WBC precursors) with fibrosis
 Increased abnormal megakaryocytes
 Spleen
 Enlargement due to extramedullary hematopoiesis
Genetics:
 JAK2 mutation is found in >95% of patients with PV: The most common mutation (JAK2 V617F; gain of function) results in constitutive activation of JAK2 activation of downstream signaling pathways  proliferation and survival

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Essential thrombocytosis

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Clinical Features: Characterized by a sustained thrombocytosis>450,000/uL. Most cases in patients 50-60 (M=F) years with a second peak in the 30’s, particularly in women.
 More than 50% of patients are asymptomatic at diagnosis. Significant splenomegaly is less common. Vascular occlusion - Microvascular occlusion: TIAs, gangrene. Splenic or hepatic vein thrombosis (Budd-Chiari). Hemorrhage: GI tract, upper airway
Causes of reactive thrombocytosis must be excluded! ( Iron deficiency, splenectomy, surgery, infection, inflammation, metastatic cancer, and CT disorders)
 CBC results: Marked thrombocytosis; WBC count and differential are usually normal
 RBCs usually normocytic/normochromic
Morphology:
 The bone marrow is normocellular or hypercellular
 Proliferation of large megakaryocytes
Usually no significant proliferation of other celllines or fibrosis. In Peripheral blood Platelets may vary in size
Genetics: A mutation in JAK2 is found in 50% of patients with ET

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Primary myelofibrosis

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Clinical Features: Characterized by progression from initial prefibrotic phase to a fibrotic phase
 Incidence: most cases occur in patients 50-60 years (M=F). Up to 30% of patients are asymptomatic at diagnosis when splenomegaly is
detected upon routine PE or when a routine CBC reveals leukocytosis and/or thrombocytosis. In the initial stage, thrombocytosis may be marked, mimicking ET. Symptoms include fatigue, weight loss, night sweats, fever and bleeding episodes. Splenomegaly is detected in the majority of patients
 CBC results: Anemia, leukocytosis and/or thrombocytosis
Morphology:
Prefibrotic/early stage PMF:
 The bone marrow is hypercellular
 Proliferation of large, dysplastic megakaryocytes
 Increase in neutrophils and Minimal fibrosis
Fibrotic stage:
 Peripheral blood has Leukoerythroblastic reaction and teardrop RBCs. Bone marrow has Extensive fibrosis which May be devoid of hematopoietic cells
 Osteosclerosis may develop; Spleen Enlargement due to extramedullary hematopoiesis
Genetics: A mutation in JAK2 is found in 50% of patients with PMF

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Acute Myelogenous Leukemia

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Clinical Features:
AML is the most common acute leukemia in adults
80% of cases of acute leukemia in adults; median age at diagnosis is 65 yrs
 10% of cases of acute leukemia in children <10 yrs
 Incidence is approximately 3-5 cases/100,000 population
 Occasional patients present with extramedullary disease. Cutaneous or gingival infiltration most often seen with monocytic leukemia
 A localized tissue mass of leukemic cells may precede marrow disease; a myeloid sarcoma (aka chloroma or granulocytic sarcoma)
 Signs and symptoms related to cytopenia
 Weakness, infections, general fatigue, bleeding
 Fever – infection or disease-related
 CBC results: Usually anemia, neutropenia and/or thrombocytopenia
 Myeloblasts are usually present, but in some patients blasts are not found in the blood
Morphology:
 The bone marrow is typically hypercellular due to a proliferation of immature cells
 A diagnosis of AML is based on finding >20% myeloblasts in the marrow (NL 2-3%).
 Myeloblast: large cells with delicate chromatin and prominent nucleoli. The cytoplasm of myeloblasts may contain Auer rods. These distinctive rod like
structures are composed of abnormal granules. The presence of Auer rods is definitive evidence of myeloid differentiation

Genetics:
 The group of AML with recurrent cytogenetic abnormalities is characterized by mainly balanced translocations, a high rate of complete remission and favorable prognosis.
Tx: HSCT is indicated for patients with AML in first complete remission who are under the age of 60, have high risk disease, and who have an HLA matched donor. (LT RF survival is 40-50%). Allo better than auto due to graft vs. leukemia effect.


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Acute promeylocytic leukemia

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Acute promyelocytic leukemia (FAB M3) associated with t(15;17) is characterized by a proliferation of hypergranular promyelocytes, often containing
many Auer rods. tx and prog are dif. DIC asoc. propensity of abnormal bleeding.

In APL with t(15;17), the retinoic acid receptor alpha (RAR) gene on chromosome 17 fuses with a nuclear regulatory factor on chr. 15 (promyelocytic leukemia gene, PML) giving rise to a PML-RARgene fusion product. This fusion product results in inhibition of granulocyte maturation.

Front 33

Acute lymphoblastic leukemia

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Overall: 85% are precursor B cell origin, manifests as leukemia.
Presentation: B type occurs most frequently in childhood. Anemia, thrombocytopenia, and/or neutropenia due to marrow replacement. bone pain. Fever night sweats and weight loss maybe, but usually not becuase its so fast. HSM may be seen. T cell type occurs most freq in late childhood/adolescene. Typically teen boys with lymphadenopathy or a bulky anterior mediastinal mass involving thymic tissue. Can have superior vena cava syndrome. Can evolve to a leukemic picture.

Morphology/immunophenotype: blast markers like CD34, TdT and b cell markers (19, 10) or t cell markers (CD3)
Genetic findings: abnormalities in chr number (which is good). See notes for cytogenetic findings for B cell. Cytogenetics of T cell - translocations involve the TCR loc in chr 14q with a variety of partner genes.

Survival: 2 years of treatment 1/mo, 98% of kids have complete remission. 75% cured. The other 25% can get second remission.
Factors assoc with adverse prognosis (B type):
age less than 1 or greater than 10. HIgh WBC at diagnosis, slow resp to initial tx, min. residual disease after tx, certain cytogenetics.
HSCT: in adults cure is <30% if only do chemo. After all transplat for high risk ALL in 1st remission/std risk in 2nd remission is 50%. Transplant related mortality is 20-25%.

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Chronic Lymphocytic leukemia/small lymphocytic lymphoma

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Most common leukemia of adults in the western world. Median age of diagnosis is 60. Originiate from rare CD5 autoreactive B cells.

Px: nonspecific fatigue, weight loss, anorexia. Generalized lymphadenoapthy, HSM. 25% asymptomatic. 10% have nodal presentation.
- Sustained lymphoctosis at least >5000. Do Flow cytometry to confirm. If less than 5000 --> monoclonal lymphocytosis.

Complications:
1) Immunodeficiency, infections in 50% of deaths (s. pneumonia, s. aureus, h. influenzae, zoster reactivation) Hypogammaglobulinemia. Autoimmune phenomen
2) Anemia, has several causes.
3) Thrombocytopenia

Morphology: infiltrate of small mature lymphocytes in LN and bone marrow. IN peripheral blood see small round lymphocytes with scant cytoplasm. SMudge cells bc they are farigle.

Genetics - translocations are rare. Deletions of 13q, 11g, 17p, trisomy 12
Survival: A small fraction of patients tumors will transform into an aggressive lymphoma (Richters trans) which has survival <1 yr. Median survival is >10 years for pts with minimal tumor burden.

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Hairy cell leukemia

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Epi - uncommon, indolent, only 2% of all leukemia. Most common in older men (M:F 5 to 1) who present with pancytopenia and HSM.

Common presentation: infections assoc with neutropenia, fatigue from anemia, petechiae from thrombocytopenia, and abdominal fullness/early satiety from splenomegaly.
Morphology: hairy cytoplasmic projections of lumphocytes in periph and bone marrow. Neoplastic MATURE memory b cells. Bone marrow fibrosed --> dry tap. Fried egg appearance on core biopsy. Red pulp of spleen is frequently infiltrated as well.
Genetics: mutation in BRAF oncogene which leads to constitutive activation of RAF-MEK-ERK mitogen activated signaling pathway leading to cell division and differentiation.

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Follicular lymphoma

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Epi - most common indolent non-hodgkin lymphoma. Older age. Most are low grade but some later transform to the more aggressive Diffuse large B cell lymphoma.
Px: multiple lymph node sites involved otherwise asymptomatic, variable relapsing course.
Histo - mixed small and large irregular shaped lymphocytes organized in nodules attempting to recapitulate normal germinal centers.
Genetics - diagnositic hallmark is t(14:18) BCL-2 gene next to the promoter of the ig heavy chain gene. A lot of BCL-2 --> cell invulnerability to apoptosis.
Survival: median survival with tx is >90% at 5 yrs.

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Diffuse large B cell lymphoma

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Epi - 40% of all non-hodgkins lymphoma, the most common of the aggressive forms of lymphoma.
Clinical: mean age of 60 years old. Patients present with rapidly enlarging, mass at single nodal or extranodal site including GI, skin, bone, brain. May have fever, night sweats, weight loss, fatigue.
Histo: large round lymphocytes in a diffuse sheet-like pattern.
Molecular: alterations in BCL6 (tx reg req for form the formation of normal germinal centers. translocations of the BCL6 locuse at 3q27 ot muysyiond og yhr BLC6 promoter. BCL6 is subject to somatic hypermuation in normal germinal center B cells which is why it is vulnerable. DLBCL with the t(14:18) are prob from follicular lymphomas that have transformed.
Prognosis: International prognostic index (APLES). 65% 5 year disease free survival with combo monoclonal ab and intensive chemo.
HSCT: AUTO transplant indicated in relapsed aggressive

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Burkitt's lymphoma

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Clinical: primarily disease of children or HIV+ patients. Highly aggressive tumors with explosive growth.
Histo: small cells in a starry sky pattern created by macros engulfing apoptotic tumor cells, numerous mitoses.
Molecular: t(8:14) or variation which places the myc oncogene adjacent to the ig heavy chain gene promoter. too much c-myc cell cycle regulator thereby promoting proliferation.
Pathogenesis: EBV infects epithelial cells of the oropharynx and then B lymphocytes via CD21 molecules. In the B cell the linear genome of EBV circularizes to form an episome in the cell nuc, latent infection. Most patients are asymptomatic or develop inf. mono. Some patients get sustained proliferation of EBV immortalized B cells which then can get more mutations like t814. EBV transcripts also inhibit antigen presentation so that recog by cytotoxic lymphocytes is reduced
Survival: with intense chemo, 60-90% cure.
HSCT: do AUTO transplant in relapsed aggressive

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Marginal zone lymphoma/MALToma

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Clinical: localized mass at an extra-nodal site (stomach, conjunctiva, skin, lung). Indolent.
Patho: lymphoma arises in chronically inflamed tissues (either AI: thyroid, salivary glands, or infection: stomach, lung, skin, conjunctiva). Stomach, highly assoc with helicobacter pylori. Lymphoma begins as a reactive polyclonal process and over time a monoclonal B cell population emerges than gets more genetic changes (low grade maltoma.) Some low grades transform into DLBCL
Histo: acquired MALT tissue with germinal centers surrounded by expanded bands of marginal zone B cells with lymphoepithelial lesions (B-lymphocytes invading overlying epithelium)
Survival: indolent in early stages. Early gastric lesions may be treated with antibios. Local radiation or chemo.

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Hodgkin's lymphoma

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Aggressive B cell lymphoma.
Patho: no usual b cell antigens but molecular studies show igH gene rearrangements which indication B cell lineage.
Clinical: One of the most common cancers of uoung adults, particuarly young women, median age 32. Arises in a single node or node chain. Spread is PREDICTABLE: Ln to spleen to Live to bone marrow.
Histo: infrequent giant atypical cells called reed-sternberg cells (large binucleated or polylobated nuclei with striking eosinophilic nucleoli surrouned by chromatin clearing resembling viral inclusions) which are surrounded by reactive lymphocytes, histiocytes, and eosinophils.
Survival: usually curable with multiagent chemo.
HSCT: AUTO transplant in early relapse -> 70-85% 5 year survival

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Mycosis Fungoides

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Most common T-cell lymphoma and most common cutaneous lymphoma. Indolent to aggresive.

Clinical: Older adults. Begins as a flat red rash patch then thickens to a palpable plaque and then to a tumor nodule. May transform into Sezary sundrome with blood, lumph node involvement and a rash covering the entire body.
Histo: classic shows clusters of medium sized lympho with convoluted nuclei invading the epidermis with a band like infiltrate of CD4 T helper cells in the UPPER DERMIS.
Survival: localized therapy can keep the skin disease under control for years but sezarys syndrome is baaad.

Front 42

Hereditary Nonpolyposis colorectal cancer (genetics)

Back 42

Germline mutations in MSH2 and MLH1 mismatch repair genes (cant repair/recognize DNA damage)

Front 43

Ataxia telangiectasia

Back 43

Neuronal degeneration in childhood (ataxic dyskinetic syndrome). ATM is a kinase that sense DNA ds break and phosphorylates p53 (so it can do its thang).
Mutations in ATM inc the sensitivity to x-ray induced DNA damage.

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BCR-ABL details

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The novel chimeric protein in CML, generated by translocateion of the ABL gene on chr 9 to the breakpoint cluster region (BCR) on chromosome 22.
- ABL is a non-receptor tyrosine kinase that participates in signal transduction pathways of hematopietic cells. BCR-ABL is constitutively active bc it can always homodimerize.
- Gleevec (imatinib mesylate) blocks the ATP binding site of ABL.

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APC and Beta-catenin and diseases

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- components in signaling pathway activated by ligand binding to a cell surface receptor called WNT.
- B-catenin is a txn factor that regulates ce proliferation AND adhesion
- if no wnt ligans, APC suppresses cell proliferation by promoting the degradation of B-catenin.
- Familial adenomatous polyposis: deletion of one APC gene and some mutations, leads to hundreds and thousands of colonic polyps. 100% risk of colon cancer. avg age 39
- Attenuated FAP. 50% risk of cc, age 55.
- Rare, gardner syndrome: osteomas, desmoids, skin cysts
- Turcot syndrome (rare): 2/3 have APC muts and get medullablastoma. the other 1/3 have an HNPCC mut and get glioblastomas.

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MYC and miRNAs

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miRNA - noncoding 22 bp ss RNA that function at post transcriptional level to silence specific genes.
- MYC suppresses miR-23a/b to increase glutaminolysis

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Retinoblastoma

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RB gene - ubiquitous nuclear phosphoprotein that regulates cell cycle.
- Hyophosphorylated RB binds and sequesters E2F tx factor (which prevents the synth of S phase stuff like cyclin E).
- HypoP RB also recruits histone modifying enzymes that make the E2F gene less accessible to txn factors.
- Growth factors timulate signaling pathways leading to hyperphosphylation of RB, release of E2F and subsequent transcription of S phase genes.

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Bcl2 assoc, mech

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- antiapoptotic protein in follicular lymphoma through the t(14:18) translocation
- Bcl2 prevents/controls release of cytochromc c relase from mito (if release causes apoptosis)

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Angiogenesis in tumors

Back 49

- Max d is 1-2 mm. cancer cells develop the ability to stimulate angiogenesis once they get bigger than that
- HIF1alpha under hypozia is not hydroxylate and is not a stable txn factor VEGF
- gliobastoma multiforme produces VEGF.
- anti-angiogenic factor, Von Hippel Lindau (del of chr3) in renal cell carcinoma

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Multiple myeloma

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HSCT: AUTO stem cell transplant is the standard of care for smptomatic multiple myeloma. 5 year overall survival w/ trans is 45%.

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Acute Graft vs. host disease

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Donor T-cells infiltrate host tissue and create a cytokine storm
Typically affected organ systems are Skin, GI tract, and Liver
Diagnose by biopsy of affected organ
Traditionally defined as occurring before day 100 after transplantation
Now defined by clinical features
Skin: A pruritic maculopapular rash can affect the palms, soles, or
face and may become generalized.
Gut/ liver: Nausea, vomiting, abdominal pain, diarrhea, bloody
stool, and jaundice may occur.
Prophylaxis prior to transplant with Methotrexate + either Cyclosporine or Tacrolimus
Treatment after acute GVH occurs is with high dose steroids (2 mg/kg), or antithymocyte globulin (ATG)
Steroid Refractory acute GVH has very poor survival due to high risk of opportunistic
infections and organ damage from GVH
The principal risk factor is HLA mismatch, but GVHD may occur despite an HLAmatched donor and the use of preventive measures. If prophylaxis is not provided,
serious acute GVHD affects almost 100%
The incidence of GVHD can be reduced by in vitro T-cell depletion of the graft before
transplantation, but this does not improve disease-free survival, because the rates of
graft rejection and relapse increase.

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Chronic graft vs. host disease

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Affects 40-80% of long term survivors of alloSCT
Loss of Self Tolerance
Mimics signs of autoimmune disorders, like scleroderma or Sjögren’s syndrome.
Skin, nail, mouth, eye, liver, lungs commonly affected
Can present as keratoconjunctivitis sicca, esophageal stricture, malabsorption,
cholestasis, cytopenias, bronchiolitis, and generalized immunosuppression.
Previously defined as occurring >100 days after transplant, but now clinically defined
Treatment with corticosteroids may be needed for two years or longer

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Complications of HSCT: Sinusoidal obstruction, Hepatic Veno-occlusive diease

Back 53

Clinical triad of weight gain +/- ascites, tender hepatomegaly, and jaundice
Caused by conditioning regimen toxicity, and results in damage to endothelial
cells, sinusoids and hepatocytes
Risk factors
Patients with liver disease prior to transplant
Heavy chemotherapy pre-treatment prior to transplant
Prolonged, elevated Busulfan levels
>12 Gray total body irradiation
Diagnosed by liver ultrasound and biopsy
Occurs 8-10 days after prep regimen. High mortality rate
New drug Defibrotide (adenosine receptor agonist) has response rate of 36%

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Complications of HSCT: pulm toxicity

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Occurs within 4 months of transplant
Mortality rates of 60%
Differential Diagnosis
Idiopathic pneumonia syndrome
Diffuse alveolar hemorrhage
Obstructive Airway Disease (Bronchiolitis obliterans)
Treatment of above diseases is mostly supportive, but may include high dose
steroids
Differentiate from “Engraftment Syndrome”
During neutrophil recovery
High fever, fluid retention, and diffuse pulmonary infiltrates

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Langerhans cell histiocytosis: classification, common micro

Back 55

Classification: Single or multiple lesions. Unisystem or multisystem.
Micro: Proliferation of Langerhans cells with abundant, often vacuolated
cytoplasm (image 1)
 Nuclei: linear grooves and minimal atypia
 LCs may be admixed with eosinophils (usually prominent), lymphocytes,
plasma cells and neutrophils
 Electron Microscopy: Characteristic Birbeck granules in the cytoplasm
(image 2)
o Pentalaminar tubules with a dilated terminal end (tennis racket-like)
o Contain protein langerin
 Phenotype: LC express HLA-DR, S100, and CD1a

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LCH Multifocal, multisystem

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Patients with multisystem disease and involvement of bone marrow, liver
and lung are regarded as high risk
1) Multifocal multisystem LCH (Letterer-Siwe Disease)
o Infants and children <2 years old, occasional adults
o Skin, bone, liver, spleen and bone marrow are preferentially
involved
o Aggressive clinical course; most patients require
chemotherapy

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Unifocal unisystem vs. multifocal unisystem

Back 57

Uni -
 Most commonly affects the skeleton of older children
and adults
 Medullary cavities of bone: calvarium, ribs and femur
 Other sites skin and lymph node
 Clinical correlate: indolent, may regress spontaneously

Multi
Young children
 Multiple erosive bone lesions
 Exophthalmos
 Involvement of the posterior pituitary stalk of the
hypothalamus leads to diabetes insipidus (DI)
 DI is the most common endocrine abnormality in
LCH
 Clinical correlate: prognosis depends on sites of

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Pulmonary LCH

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Adult smokers
o Chronic interstitial lung disease with nodular and cystic lesions
o Present with nonproductive cough, dyspnea, fever, weight loss
o May be discovered incidentally on CXR
o Lesions regress upon smoking cessation
 Thought to represent a reactive, non-clonal process

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Major fxns of spleen

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1) Phagocytosis of blood cells (senescent and abnormal) and particulate matter. Abnormally shaped or antibody-coated RBCs are phagocytosed by macrophages. Macrophages also remove bacteria from the blood.
2) Antibody production – dendritic cells in the PALS trap and
present antigens to T-cells, leading to activation and proliferation
of B and T lymphocytes and antibody-producing plasma cells.
3) Hematopoiesis – normal prior to birth; can be seen after birth in response to marrow failure or in myeloproliferative neoplasms
4) Sequestration of formed blood elements – storage of blood, especially RBCs

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Causes of splenomegaly

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White pulp: Reactive hyperplasia - Autoimmune disorders, infectious mononucleosis,
parasitic infections, Infiltrative diseases - Lymphoma,
amyloidosis
Red Pulp: Macrophages of red pulp - Storage
disorders (Gaucher’s, Niemann-Pick)
Hyperplasia of phagocytes – hemolytic
anemia (hereditary spherocytosis)
Sinusoids - Extramedullary
hematopoiesis (myelofibrosis, marrow
replacement)
Vascular congestion – portal
hypertension
Both Red and White Pulp- Some types of lymphoma

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Thymoma

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Thymoma is the most common anterior mediastinal primary neoplasm in adults, rarely seen in children.
Commonly present between ages 30y and 50y.
 Approximately 50% of patients are asymptomatic at diagnosis and are discovered incidentally upon imaging for an unrelated purpose
 Symptomatic patients:
o Myasthenia gravis
o Substernal pain, dyspnea, cough, superior vena cava
syndrome
o Pure red cell aplasia
Morphology:
 Neoplasm of thymic epithelial cells with sparse component of
thymocytes
o Variable cytologic features
 Categorized based on cytologic (benign or malignant) features and
presence of capsular and surrounding tissue invasion
o Noninvasive thymoma
o Invasive thymoma
o Thymic carcinoma

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Oncogenes for self-sufficiency

Back 62

ERB B2 Breast cancer Gene amplification
BCR-ABL, Chronic myelogenous
leukemia, t(9;22)
Ras, Multiple types, Gene mutation
c-myc, Burkitt lymphoma, t(8;14)

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Insensitivity to anti-growth signals

Back 63

Signal Cancer Mechanism
G1 checkpoint, Retinoblastoma, Loss of both Rb alleles
DNA damage, Many cancers, Loss or mutation of p53
TGFβ, Pancreatic (100%) and Colon cancer (83%), Mutations in the signaling pathway

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Strategies for evading apoptosis

Back 64

Overexpression of apoptosis inhibitors
(e.g., Bcl-2)
 Mutations in pro-apoptotic regulators
(e.g., p53 mutations)
 Abnormal activity of prosurvival signaling
pathways (e.g., PTEN mutations)

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Sustained angiogenesis in cancer

Back 65

HIF1α under normoxia:
- hydroxylated
- is bound by the Von HippelLindau protein & degraded
- is a short-lived protein
HIF1α under hypoxia:
- not hydroxylated
- is a stable transcription factor
- gene targets include VEGF
(vascular endothelial growth
factor)

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Osteogenic Sarcoma

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1. Malignant neoplasm of osteoblasts
2. Teen-agers and young adults; other age group is >60 years (generally a
complication of Paget disease)
3. Imaging findings:
a) irregular bone destruction which may include break-through of cortex and
associated soft tissue mass
b) periosteal reaction “sunburst” (spiculated)
4. Most frequent location is about the knee (distal femur or proximal tibia)
5. Pathology:
Gross: gray-white mass; may be hard
Microscopic: malignant osteoblasts forming bone (usually in a lace-like or filigree
pattern; rarely resembling normal bony trabeculae)
6. Lungs most frequent site of metastasis (If the number of lung metastases is small,
may be resectable); metastasis to other bones common
7. Treatment: complete surgical resection; chemotherapy (may be given preoperatively to reduce tumor volume)

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Chondrosarcoma

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1. Malignant neoplasm of chondrocytes
2. Patients usually adults (rarely seen before age 40)
3. Imaging findings:
a) irregularly destructive lesion within bone
b) generally lytic (radiolucent)
c) may have soft tissue extension which has radiodensity of cartilage with speckled
calcification (not bone)
4. Pathology:
Gross: Often recognizable as cartilage, with translucent tissue and lobulated periphery (calcification frequently at the periphery)
Microscopic: varying degrees of differentiation: well-differentiated form looks much
like ordinary hyaline cartilage, but cells have increased nuclear size; poorly differentiated forms have greater numbers of cells, less matrix and increasing variation in nuclear size, shape and chromatin density
5. Survival strongly inversely correlated with numerical grade (highest % survival for Grade I lesions)
6. Likelihood of malignant transformation closely related o anatomic location (more
likely in axial skeleton or proximal portions of long bones, less likely in small bones
of hands and feet)

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Ewing Sarcoma

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1. Malignant neoplasm of primitive cells (current evidence favors a primitive mesenchymal cell line with neural features)
2. Children and young adults; distal femur/ proximal tibia
3. Imaging findings:
a) irregularly destructive, lytic lesion which may have a disproportionately large soft tissue mass relative to the amount of boneinvolvement
4. Pathology:
Gross:gray-white tumor
Microscopic: “round-cell” tumor of uniform cells with scanty cytoplasm and
moderate-sized, hyperchromatic nuclei; may grow in sheets, frequently filling up marrow space; no matrix produced by cells
5. Characteristic chromosomal translocation 11:22
a) this translocation also seen in primitive neuroectodermal tumor [PNET] which is felt to have similar origin as Ewing
b) fusion gene (FLI1-EWS)
6. Differentil diagnosis includes other “round-cell”tumors

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Liposarcoma

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1. Adults, principally 5th to 7th decade
2. Anatomic location chiefly retroperitoneum, deep tissues of thigh
3. Pathology
Gross: often more gray-white, myxoid (gelatinous) than mature fat (except for
well-differentiated variant)
Microscopic variants -
a) Well-differentiated - may resemble benign lipoma
b) Myxoid - abundant mucopolysaccharide in stroma, "chicken-wire"
vascular pattern
c) Round cell - may resemble other round cell tumors (lymphoma, Ewing's
sarcoma)
d) Pleomorphic - undifferentiated, anaplastic, bizarre cells
4. Myxoid and round cell variants have same chromosomal translocations
t(12;16)(q13;p11) and t(12;22)(q13;q12) and are commonly considered together
5. Best prognosis for well-differentiated variant; worst with pleomorphic forms
6. Recurrence common (about 50%)

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Rhabdomyosarcoma

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1. More common in children (except for pleomorphic variant)
2. Principally head and neck or urogenital sites (children and deep soft tissue (adults)
3. Pathology:
Gross: usually gray-white, infiltrative (exception is botryoid variant which is polypoid and has a grape-like texture)
Microscopic variants -
a) Embryonal - round to oval, generally small cells; some areas suggestskeletal muscle differentiation with larger, eosinophilic cells which may have cross-striations
b) Botryoid - small dark cells usually closely grouped beneath overlying normal mucosal epithelium (common form in urogenital tract)
c) Alveolar - primitive dark cells arranged among collagenous trabeculae with spaces suggesting alveolar spaces of lung
d) Pleomorphic - large, bizarre cells with abundant eosinophilic cytoplasm (more common in adults)
4. Immunohistochemical demonstration of muscle-related antigens (desmin, actin) or election microscopy (to demonstrate myofilaments) may be necessary to distinguish from other soft tissue sarcomas
5. Prognosis for subtypes in descending order (best to worst): Botryoid, embryonal, pleomorphic, and alveolar
6. Clinical course: Success of surgical resection depends on anatomic site (surgery on sarcomas of extremities more likely to be complete than those involving the orbit or cranial foramina); 20-40% develop metastases; about 65% cure rate .

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Synovial Sarcoma

Back 71

1. Cell of origin uncertain, but probably not synoviocytes
2. Only 10% occur adjacent joints; most are deep soft tissue
3. Young adults, early middle-age (90% less than 50 years)
4. Males more often affected than females
5. Lower extremity most often involved (70%), commonly knee
6. Presents as mass lesion; may grow more slowly than other soft tissue
malignancies, but intrinsically aggressive
7. Translocation t(X;18)(p11;q11); fusion gene SYT-SSX
8. Pathology:
Gross: Mass, usually tan to gray; may have calcification
Microscopic:
a) Typically biphasic, with glandular-type epithelial cells and spindled cells
b) Epithelial-type cells express cytokeratin; may have mucus
c) Spindle cells may also express cytokeratin (particularly helpful when tumor
is the monophasic spindle-cell type)
9. Five year survival ~50% (only 20% at ten years)
10. Good prognostic features:
a) Tumor size less than 5 cm diameter
b) Early clinical stage
c) Age < 10 years at presentation

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Undifferentiated Pleomorphic Sarcoma

Back 72

1. High-grade, pleomorphic neoplasm without matrix production
2. Adults over 40 years; incidence greater with older age
3. Majority involve lower extremity
4. MFH in bone:
a) Lytic, irregularly destructive lesion
b) Frequently in femur
c) Pain is major presentation, less often swelling
d) Necrosis common, may be extensive
5. MFH in soft tissue:
a) Deep-seated tumor
b) More likely to present as mass than with pain
6. Pathology:
a) Gross: generally large, gray-white
b) Microscopic: mixed spindle cell and polygonal cell population, arranged in
interwoven fascicles (storiform – “mat-like”) with conspicuously pleomorphic
nuclei scattered throughout
7. Currently thought that many cases previously diagnosed as undifferentiated ple
omorphic sarcoma may be pleomorphic, poorly-differentiated variants of other
cell lineage (e.g., myogenic); however, the entity of MFH is still recognized
8. Still helpful as a diagnostic category, particularly for MFH of bone, which has a
well-known association as a complication of bone infarct