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PATHOLOGY 2 > Hematopoietic and Lymphoid system > Flashcards

Hematopoietic and Lymphoid system Flashcards

1
Q
  1. Anemias of diminished erythropoiesis:

LINEAGE SPECIFIC MARKERS

A
  • Granulocytes: CD13, CD15, CD33
  • Erythroid: glycoprotein 4
  • Monocytes: CD14
  • B-cells: CD19, CD20, CD49a, PAX
  • T-cells: CD2, CD3, CD4, CD5, CD8
  • NK-cells: CD10, CD16, CD57, perforin, TIA
  • megakaryocyte: CD64
  • progenitor: CD34, CD117, TdT
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2
Q
  1. Anemias of diminished erythropoiesis:

DETERMINATION OF ANEMIAS

A
  • Decreased level of:
    • Hemoglobin: 12-17mg/dl
    • Hematocrit: 33-50%
    • RBCs: 4-5million
  • Pathogenesis:
    • Blood loss anemia: acute/chronic
    • Hemolysis anemia: intra/extravascular
    • Decreased synthesis anemia: iron insufficiency
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3
Q
  1. Anemias of diminished erythropoiesis:

IRON DEFICIENCY ANEMIA

A

PATHOGENESIS:
- chronic blood loss
- low intake
- increased demand
- malabsorption syndromes
- iron stores depleted ⇒ decreased serum iron ⇒ rise in serum transferritin ⇒⇒ microcytic hypo chromatic anemia (decreased MCV, MCHC)
CLINICAL FEATURES:
- mild, asymptomatic, weakness, listlessness, pallor
- koilonychia, pica, restless leg syndrome
DIAGNOSIS:
- inreased: platelet count, EPO, total iron-binding capacity
- decreased: serum ferritin, iron, transferritin saturation
- hypochromic and microcytic RBCs

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4
Q
  1. Anemias of diminished erythropoiesis:

MEGALOBLASTIC ANEMIA

A

= folic acid & vitamin B12 deficiency (required for DNA synthesis)
PATHOGENESIS:
- cellular gigantism: defect in DNA synthesis ⇒ DNA replication but no division
- Nuclear-cytoplasmic asynchrony: RNA + organelle synthesis normal
- Ineffective hematopoiesis: pancytopenia (many megaloblasts undergo apoptosis in bone marrow)
MORPHOLOGY:
- Hypercellular bone marrow
* megaloblasts: large erythroid precursors with delicate, finely reticulocyte nuclear chromatin
* Giant metamyelocytes: granulocytes precursors
* Large megakaryocytic with bilobed nuclei
- Peripheral blood:
* hypersegmented neutrophils
* RBCs large, egg-shaped macro-ovalocytes, increased MCV

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5
Q
  1. Anemias of diminished erythropoiesis:

FOLATE DEFICIENCY ANEMIA

A 
RISK FACTORS:
 - poor diet
 - increased metabolic needs
 - malabsorption disorders
 - drugs
PATHOGENESIS:
 - folate ⇒ dihydrofolate ⇒ tetrahydrofolate
CLINICAL FEATURES:
 - insidious onset, no specific symptoms
DIAGNOSIS:
 - blood smear, bone marrow smear
 - measure RBC and serum folate level
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6
Q 
16. Anemias of diminished erythropoiesis:
PERNICIOUS ANEMIA (VITAMIN B12 DEFICIENCY)
A
  • mostly due to long-standing malabsorption
    PATHOGENESIS:
  • Autoimmune reaction against parietal cells + intrinsic factor ⇒ gastric mucosal atrophy
    • parietal canalicular AB, blocking AB, IF-B12 complex AB
  • after gastrectomy, ill resection or disorders affecting terminal ileum
  • required for recycling of tetrahydrofolate
    CLINICAL FEATURES:
  • demyelinating disorder of peripheral nerves + spinal cord
  • pallor, fatigue, dyspnea
  • risk to develop gastric carcinoma
    DIAGNOSIS:
  • low B12 level
  • normal/elevated folate level
  • serum AB to IF
  • megaloblastic anemia
  • leukopenia + hypersegmented granulocytes
  • dramatic reticulocyte response to B12 admin.
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7
Q
  1. Anemias of diminished erythropoiesis:

APLASTIC ANEMIA

A
  • multipotent myeloid stem cells suppressed ⇒ bone marrow failure ⇒ pancytopenia + anemia
    PATHOGENESIS:
  • idiopathic/exposure to myelotoxic agent
  • viral infection
  • autoreactive T cells attack bone marrow cells
  • genetic correlation⇒ inherited defect in telomerase
    MORPHOLOGY:
  • hypocellular bone marrow (only lymphocytes and plasma cells)
  • fatty change in liver
  • RBCs normochromic and normocytic
  • less reticulocytes
    CLINICAL FEATURES:
  • thrombocytopenia ⇒ hemorrhages (petechia + ecchymoses)
  • granulocytopenia ⇒ bacterial infections
  • no splenomegaly
    TREATMENT:
  • bone marrow transplant/ transfusion
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8
Q
  1. Anemias of diminished erythropoiesis:

ANEMIA OF CHRONIC DISEASE

A
  • associated with:
    • chronic microbial infection
    • chronic immune disorders
    • neoplasms
      PATHOGENESIS:
  • high level of hepcidin ⇒ blocks transfer of iron to erythroid precursors by down regulating ferroprotein in macrophages
  • pro-inflammatory cytokines ⇒ high level of hepcidin
  • inflammation ⇒ block EPO synthesis in kidney⇒ lower RBC production
    CLINICAL FEATURES:
  • RBCs hypochromatic and microcytic
  • increased storage iron in bone marrow
  • increased ferritin
  • decreased total iron-binding capacity
    TREATMENT:
  • EPO + iron administration
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9
Q
  1. Anemias of diminished erythropoiesis:

MYELOPHTHISIC ANEMIA

A
  • due to invasive infiltration of bone marrow by tumors
  • associated with metastatic breast, lung + prostate cancer or TB, lipid storage disease, osteosclerosis
    MORPHOLOGY:
  • teardrop-shaped RBCs
  • thrombocytopenia
  • leukoerythroblastosis
    TREATMENT:
  • underlying cause
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10
Q
  1. Anemia of blood loss:

HEMOLYTIC ANEMIA

A 
SHARED FEATURES:
 - decreased RBC lifespan
 - compensatory increase in erythropoiesis
 - retention of degradation products
 - erythroid hyperplasia in BM 
 - extramedullary hematopoiesis
INTRAVASCULAR HEMOLYSIS:
 - due to mechanical forces
 - due to biochemical or physical agents⇒ damage RBC membrane
 - leads to hemoglo binemia, hemoglobinuria, hemosideroinuria, hyperbilirubinemia, jaundice
 - severe⇒ acute tubular necrosis
 - haptoglobin exhausted
 - increased LDH in plasma
EXTRAVASCULAR HEMOLYSIS:
 - in spleen or liver
 - lead to jaundice + pigment gallstones
 - decreased haptoglobulin
 - LDH elevated
 - splenomegaly
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11
Q
  1. Anemia of blood loss:

HEREDITARY SPHEROCYTOSIS

A 
- inherited defect in RBC membrane ⇒ spherocytes
PATHOGENESIS:
 - spectrin (alpha and beta) ⇒ ankyrin ⇒ protein 3
 - ankyrin has most mutations
MORPHOLOGY:
 - spherocytes- dark red, no central pallor
 - compensatory hyperplasia of RBC progenitors and reticulocytes
 - systemic hemosiderosis
 - cholelithiasis
CLINICAL FEATURES:
 - anemia
 - splenomegaly
 - jaundice
 - aplastic crisis
TREATMENT:
 - splenectomy
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12
Q
  1. Anemia of blood loss:

SICKLE CELL ANEMIA pathogenesis

A

PATHOGENESIS:

  • mutation in beta-globin gene ⇒ sickle hemoglobin HbS
  • hypoxia, dehydration, acidosis ⇒ sickle shape ⇒ influx of calcium ⇒ loss of K+ and water ⇒ damage ⇒ irreversible
  • other factors influencing sickling in vivo:
    • other hemoglobin (HbC, HbF)
    • intracellular concentration of HbS
    • transit time of RBC through microcirculation
  • consequences: chromic hemolytic anemia (lifespan 20d), widespread microvascular obstruction
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13
Q
  1. Anemia of blood loss:

SICKLE CELL ANEMIA morphology + clinical features

A 
MORPHOLOGY:
 - fatty changes in heart, liver, renal tubules
 - hyperplasia of erythroid progenitors
 - splenomegaly
 - hemosiderosis, gallstones
 - parvovirus B12 infection
CLINICAL FEATURES:
 - chronic hemolysis, hyperbilirubinemia and reticulocytosis
 - vaso-occlusive crisis:
   * bone marrow ⇒ infarction
   * acute chest syndrome
   * stroke
   * moya-moya + priapism
 - aplastic crisis:
   * sudden decrease in RBC production
TREATMENT:
 - hydroxyurea, opioids, antibiotics, oxygen + fluids
 - BM transplant, blood transfusion
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14
Q
  1. Anemia of blood loss:

THALASSEMIA’S

A 
PATHOGENESIS:
 - autosomal codominant inherited disorder
 - mutation that decreases synthesis of alpha or beta globin chains
MORPHOLOGY:
 - skeletal deformities
 - hepatosplenomegaly
 - lymphadenopathy
 - cachexia
 - hemosiderosis
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15
Q
  1. Anemia of blood loss:

ALPHA-THALASSEMIA

A
  • less frequent; deletion in 4 areas of genes
  • loss of 1 gene: silent carrier
  • loss of 3: excess beta-globin ⇒ stable HbH and HbBart
  • loss of 4: lethal in utero (RBC has no O2 carrying capacity)
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16
Q
  1. Anemia of blood loss:

BETA-THALASSEMIA

A

Associated mutations:
- B0= no beta globin chains produced
- B+ = reduced beta global number produced
TYPES:
- B-thalassemia minor
- B-thalassemia intermedia
- B-thalassemia major
MORPHOLOGY:
- B-thalassemia minor: microcytic + hypochromic
- B-thalassemia major: microcytosis, hypochromia, piokilocytosis, anisocytosis
MUTATION:
- mutation leads to RNA splicing
CAUSE OF ANEMIA:
- reduced synthesis of B-globin ⇒ less HbA ⇒ poorly hemoglobinized RBC prod. ⇒ hypochromic and microcytic
- imbalance of a- and b-globin ⇒ excess unpaired a-globin ⇒ insoluble precipitates ⇒ damage membrane

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17
Q
  1. Anemia of blood loss:

THALASSEMIAS clinical features

A
  1. B-thalassemia minor:
    - asymptomatic
    - normal life expectancy
    - decreased HbA, increased HbA2 levels
  2. B-thalassemia intermedia:
    - anemia moderate
    - B4-tetramers
  3. B-thalassemia major:
    - growth retardation
    - cardiac dysfunction due to secondary hemochromatosis
    - treatment: bone marrow transplant
    - decreased HbA, increased HbF
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18
Q
  1. Anemia of blood loss:

GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

A
  • GSH normally inactivates endo- and exogenous oxidants in RBCs ⇒ abnormality ⇒ hemolytic anemia
    PATHOGENESIS:
    • G6PD A mutation on X chromosome
    • infectious agents or drugs ⇒ oxidants attack RBC hemoglobin ⇒ denature + precipitate ⇒ Heinz bodies ⇒ damage cell membrane ⇒ intravascular hemolysis
    • less damaged cells ⇒ splenic macrophages try to remove Heinz bodies ⇒ bite cells ⇒ trapped in spleen ⇒ extravascular hemolysis
      CLINICAL FEATURES:
    • some normal, some G6PD deficient RBCs
    • males have a more severe form⇒ X linked
    • unfavorable lyonization ⇒ large number of deficient cells
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19
Q
  1. Anemia of blood loss:

IMMUNOHEMOLYTIC ANEMIA

A
  • autoimmune disease against RBC membrane ⇒ hemolytic anemia
  • antibodies produced ⇒ spontaneous/ induced by exogenous agents
    CLASSIFICATION:
    1. nature of the antibody
    2. presence of predisposing factors
  • warm antibody/ cold antibody
    DIAGNOSIS:
  • indirect Coombs test⇒ detection of antibodies/ complement on RBCs
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20
Q
  1. Anemia of blood loss:

WARM ANTIBODY IMMUNOHEMOLYTIC ANEMIA

A
  • caused by IgG⇒ 37 degrees
  • primary ⇒ idiopathic
  • secondary ⇒ B cell neoplasm, autoimmune disorder, drugs
  • opsonization of RBCs by autoantibodies ⇒ erythrophagocytosis in spleen ⇒ hemolysis
  • chronic mild anemia + moderate splenomegaly
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21
Q
  1. Anemia of blood loss:

COLD ANTIBODY IMMUNOHEMOLYTIC ANEMIA

A
  • caused by IgM ⇒ 30 degrees
  • acute ⇒ mycoplasma, EBV
  • chonic ⇒ idiopathic, B cell lymphoid neoplasm
  • cells to warmer body area ⇒ IgM released ⇒ C3b remains ⇒ opsonization in spleen + liver ⇒ extravascular hemolysis
  • IgM pentavalent ⇒ cross-bind RBCs ⇒ agglutination ⇒ slugging in capillaries ⇒ Raynauds phenomenon
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22
Q
  1. Anemia of blood loss:

MECHANICAL TRAUMA

A
  • defective cardiac valve protheses ⇒ turbulent flow ⇒ traumatic hemolysis
  • Microangiopathic hemolytic anemia
    • small vessels occluded ⇒ predispose passing RBCs to mechanical damage
    • DIC, malignant HT, SLE, TTP, hemolytic uremic syndrome, disseminated cancer
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23
Q
  1. Anemia of blood loss:

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

A
  • mutation in gene PIGA ⇒ codes for membrane associated proteins PIG ⇒ prevent spontaneous system activation
  • no PIG ⇒ no protein expression ⇒ increased complement ⇒ RBC lysis
  • during sleep acidic blood ⇒ increased lysis
  • PIGA is X-linked + occurs in multipoint stem cells
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24
Q
  1. Non-neoplastic disorders of myeloid and lymphoid systems: LEUKOPENIA pathogenesis
A
  1. Decreased granulocyte production:
    - bone marrow failure
    - tumor growth into bone marrow
    - cancer chemotherapy
    - sometimes isolated to only one lineage
  2. Increased granulocyte destruction:
    - immune-mediated injury
    - overwhelming bacterial, fungi infections
    - splenomegaly ⇒ sequestration and accelerated removal of neutrophils
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25
Q
  1. Non-neoplastic disorders of myeloid and lymphoid systems:
    LEUKOPENIA morphology + clinical features
A

MORPHOLOGY:
- marrow hypercellularity + excessive neutrophil destruction or ineffective granulopoiesis
- drug-induced neutropenia suppresses granulopoiesis
CLINICAL FEATURES:
- malaise, chills, fever
- weakness, fatigue
- ulcerating, necrotizing in oral cavity or pharynx
TREATMENT:
- remove offending drug
- control infection
- G-CSF administration

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26
Q
  1. Non-neoplastic disorders of myeloid and lymphoid systems:
    REACTIVE LEUKOCYTOSIS classification
A
  1. Neutrophilic leukocytosis:
    - acute bacterial infections
    - sterile inflammation
  2. Eosinophilic leukocytosis:
    - allergies, allergic skin diseases
    - parasitic infection
    - drug reaction
    - malignancies
    - collagen-vascular disorders
    - atheroembolic disease
  3. Basophilic leukocytosis:
    - myeloproliferative disease
  4. Monocytosis:
    - chronic infection
    - bacterial endocarditis
    - collagen vascular disease
    - IBD
  5. Lymphocytosis:
    - chronic immunologic stimulation
    - viral infection
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27
Q
  1. Non-neoplastic disorders of myeloid and lymphoid systems:
    INFECTIOUS MONONUCLEOSIS pathogenesis
A
  • Epstein-Barr virus
  • transmitted through oral contact
  • infect oropharynx ⇒ LN ⇒ infects mature B cells ⇒ polyclonal activation + proliferation ⇒ secrete AB
  • virus specific CD8+ T cells
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28
Q
  1. Non-neoplastic disorders of myeloid and lymphoid systems:
    INFECTIOUS MONONUCLEOSIS morphology + clinical features
A 
MORPHOLOGY:
  - peripheral blood leukocytosis
  - lymphadenopathy
  - enlarged spleen + lymphocyte infiltrate
  - lymphocyte infiltrate in liver
CLINICAL FEATURES:
  - flu-like symptoms
  - resolves 4-8 weeks
COMPLICATIONS:
  - hepatic dysfunction
  - jaundice
  - disturbed appetite
  - CNS, kidneys, bone marrow, lungs, eyes, heart and spleen involvement
DIAGNOSIS:
  - monospot test: heterophil anti-sheep RBC AB
  - rising titer
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29
Q
  1. Non-neoplastic disorders of myeloid and lymphoid systems:
    ACUTE NON-SPECIFIC REACTIVE LYMPHADENITIS
A
  • inflamed nodes swollen, grey-red + large germinal centers
  • overlying skin red
  • infiltrative neutrophils
  • severe infection ⇒ follicular centers necrotize
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30
Q
  1. Non-neoplastic disorders of myeloid and lymphoid systems:
    CHRONIC NON-SPECIFIC LYMPHADENITIS
A
  1. Follicular hyperplasia:
    - inflammation ⇒ activate B cells ⇒ migrate into B cell follicles ⇒ GC reaction
    - causes: bacterial infection, RA, toxoplasmosis, HIV
  2. Paracortical hyperplasia:
    - immune reaction in T cell region of LN ⇒ smaller GC
    - cause: viral infection, drug-induced immune reaction
  3. Sinus histiocytosis:
    - distension of sinusoids ⇒ hypertrophy of lining endothelial cells + infiltrating macrophages
    - cause: LN draining cancers
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31
Q
  1. Non-neoplastic disorders of myeloid and lymphoid systems:
    CAT-SCRATCH DISEASE
A
  • self-limited lymphadenitis
  • cause: Bartonella henselae
    SYMPTOMS:
    • regional lymphadenopathy
    • encephalitis
    • osteomyelitis
    • thrombocytopenia
      MORPHOLOGY:
    • sarcoid like granulomas ⇒ central necrosis ⇒ abscess
    • follicles preserved
      TREATMENT: antibiotics
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32
Q
  1. Non-neoplastic disorders of myeloid and lymphoid systems:
    TOXOPLASMA LYMPHADENITIS
A
  • cause: Toxoplasma gondii
  • small proliferations ⇒ epitheloid cell clusters
  • asymptomic / flu-like symptoms
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33
Q
  1. CML and chronic myelofibrosis:

CHRONIC MYELOGENOUS LEUKEMIA pathogenesis

A
  • affects adults 25-60yrs
  • BCR-ABL fusion gene⇒ translocation (9;22) philadelphia
  • lineage: granulocytic, erythroid, megakaryocytic and B cell precursors
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34
Q
  1. CML and chronic myelofibrosis:

CHRONIC MYELOGENOUS LEUKEMIA morphology

A
  • elevated leukocyte count
  • circulating cells: neutrophils, metamyelocytes, myelocytes
  • small amount of myeloblasts
  • hyper cellular bone marrow⇒ increased granulocytes + megakaryocyte precursors
  • enlarged spleen ⇒ extra medullary hematopoiesis
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35
Q
  1. CML and chronic myelofibrosis:

CHRONIC MYELOGENOUS LEUKEMIA clinical features

A
  • fatigue, weakness, weight loss, increased WBC count, leukocytosis
  • splenomegaly ⇒ abdominal discomfort
  • slow progressive disease
  • increased anemia, thrombocytopenia, cytogenic abnormalities, blast crisis
  • excessive bone marrow fibrosis
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36
Q
  1. CML and chronic myelofibrosis:

CHRONIC MYELOGENOUS LEUKEMIA therapy

A
  • chemotherapy ⇒ decreased WBC count
  • gene targeted therapies (Gleeve = imatinib mesylate)
  • resistant disease ⇒ hematopoietic stem cell transplantation
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37
Q
  1. CML and chronic myelofibrosis:

PRIMARY MYELOID FIBROSIS pathogenesis

A
  • fibroblasts ⇒ non-neoplastic
  • fibroblast proliferation due to PDGF and TGFb released from neoplastic megakaryocytes ⇒ collagen ⇒ fibrosis ⇒ pancytopenia+ extra medullary hematopoiesis
  • JAK2/V617F mutation ⇒ proliferation
    1. cellular phase ⇒ increased WBC and platelets
    2. fibrotic phase
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38
Q
  1. CML and chronic myelofibrosis:

PRIMARY MYELOID FIBROSIS morphology

A
  • peripheral blood smear:
    • poikilocytes (tear drop RBCs)
    • leukoerythroblastosis (nucleated erythroid precursors)
    • large platelets
  • extramedullar hematopoiesis
  • splenomegaly
  • hepatomegaly
  • hypocellular + fibrotic bone marrow
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39
Q
  1. CML and chronic myelofibrosis:

PRIMARY MYELOID FIBROSIS clinical features

A
  • anemia + thrombocytopenia
  • hyperuricemia + gout
  • thrombotic + hemorrhagic episoides (eccymoses)
  • splenic infarctions
  • survival 4-5yrs
    TREATMENT:
    • chemotherapy
    • stem cell transplant
    • transfusion
    • splenectomy
40
Q
  1. Polycythemia vera, Essential thrombocythemia:

ESSENTIAL THROMBOCYTHEMIA

A
  • predominance: female - middle ages
  • thrombocytosis ⇒ increased platelet count
    PATHOGENESIS: JAK2 mutation
    MORPHOLOGY:
    • bone marrow atypical + huge megakaryocytes
      SYMPTOMS:
    • thrombosis + bleeding
    • burning of hands + feet ⇒ platelet occlusion
    • splenomegaly
      TREATMENT:
    • plasmaphoresis
    • aspirin
    • hydroxyurea
41
Q
  1. Polycythemia vera, Essential thrombocythemia:

POLYCYTHEMIA VERA pathogenesis

A
  • excessive proliferation of erythroid, granulocytic + megakaryocytic elements
  • JAK2 mutation ⇒ lowers dependance of hematopoietic cells on growth factors for growth + survival
  • low levels of EPO ⇒ GF independent growth of neoplastic clone
42
Q
  1. Polycythemia vera, Essential thrombocythemia:

POLYCYTHEMIA VERA morphology

A 
- increased blood volume + viscosity ⇒ congestion
  ⇒ hepatomegaly
  ⇒ splenomegaly
  ⇒ thrombosis + infarctions
  ⇒ hemorrhages
  ⇒ hypercellular bone marrow
  ⇒ Trousseau's phenomenon
43
Q
  1. Polycythemia vera, Essential thrombocythemia:

POLYCYTHEMIA VERA clinical features + diagnosis

A
  • insidious, usually middle ages
  • plethoric + cyanotic patients
  • histamine ⇒ pruritus + peptic ulcers
  • HT
  • headache, dizziness, GI symptoms, hematemesis, melena
  • without treatment survival - 10yrs
  • treatment: chemotherapy
    DIAGNOSIS:
    • RBC count 6-10 million/microliter
    • Htc: >60%
    • basophilia
44
Q
  1. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen:
    SPLENOMEGALY consequences
A
  • anemia, leukopenia, thrombocytopenia
  • hypersplenism
  • platelets susceptible to sequestration in red pulp ⇒ increased thrombocytopenia
  • rupture
45
Q
  1. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen:
    MASSIVE SPLENOMEGALY
A
  • myeloproliferative disorders
  • chronic lymphocytic leukemia
  • hairy cell leukemia
  • lymphomas
  • malaria
  • Gaucher disease
  • primary tumors of spleen
46
Q
  1. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen:
    MODERATE SPLENOMEGALY
A
  • chronic congestion
  • acute leukemias
  • hereditary spherocytosis
  • thalassemia major
  • autoimmune hemolytic anemia
  • amyloidosis
  • Niemann-Pick disease
  • chronic splenitis
  • TB, sarcoidosis, typhoid
  • metastatic carcinoma/ sarcoma
47
Q
  1. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen:
    MILD SPLENOMEGALY
A
  • acute splenitis
  • acute splenic congestion
  • infectious mononucleosis
  • miscellaneous disorders ⇒ septicemia, SLE, intra-abdominal infections
48
Q
  1. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen:
    HYPERSPLENISM
A

= increased removal of cellular blood components
CAUSES:
- disorders ⇒ widening of splenic cords ⇒ premature destruction of normal blood components
* e.g. congestive splenomegaly, Gaucher’s disease, hemangioma
- infections
* e.g. brucellosis, CMV, echinococcus, malaria
- abnormal cellular blood components
* e.g. hereditary spherocytosis

49
Q
  1. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen:
    RUPTURED SPLEEN
A
  • due to blunt trauma to abdomen, splenomegaly
  • small capsular tear in superior pole or hilum
    SYMPTOMS:
    • pain + tenderness in upper left abdomen
    • lightheadedness
    • confusion
50
Q
  1. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen:
    SPLENECTOMY
A
  • done when there is traumatic rupture
  • no side affects
  • elevated risk of infections
  • Howell-Jolly bodies!
51
Q
  1. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen:
    THYMIC HYPERPLASIA
A
  • enlargement due to lymphoid follicles or GC becoming present in medulla
  • GC contains reactive B cells
  • in patients with Myasthenia graves or other autoimmune diseases
  • treatment: removing thymus
52
Q
  1. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen:
    THYOMA
A 
= tumors of thymus epithelial cells
CLASSIFICATION:
  1. benign 
  2. malignant 
    * TYPE 1⇒ cytologically benign but infiltrative + local aggression. Very invasive, metastasize, epithelial cells + reactive thymocytes
    * TYPE 2⇒ cytologically malignant. Fleshy, invasive masses, metastasize to lungs
MORPHOLOGY:
  - lobulated, firm, grey-white masses
  - encapsulated
  - epithelioid tumor cells + non-neoplastic thymocytes
CLINICAL FEATURES:
  - mostly in middle-aged adults
  - cough, dyspnea, SVC syndrome
53
Q
  1. Myelodysplastic syndromes:

MDS general + pathogenesis

A 
-  bone marrow replaced by clonal progeny of transformed multipotent stem cells
CAUSE:
  - idiopathic
  - after chemotherapy with alkylating agent
  - ionizing radiation therapy
PATHOGENESIS:
  - deletion / gain
   ⇒ monosomy 5 or 7
   ⇒ trisomy 8
   ⇒ deletions of 5q, 7q or 20q
54
Q
  1. Myelodysplastic syndromes:

MDS morphology + clinical features

A

MORPHOLOGY:
- megaloblastoid erythroid precursors ⇒ nuclei: budding, fragmentation, bridging
- ringed sideroblasts
- granulocyte precursors ⇒ pseudopelger guet
- small megakaryocytes with single small nuclei
CLINICAL FEATURES:
- people between 50-70yrs
- cytopenias ⇒ infections, anemia, hemorrhages
- bone marrow hypercellular
- transformation to AML
- median survival 9-29 months

55
Q
  1. Myelodysplastic syndromes:

OTHER DISEASES

A
  1. Refractory anemia RA:
    - low risk
    - with ringed sideroblasts or without
  2. Refractory cytosine with multilineage dysplasia
    - low risk
  3. Refractory anemia with excess blasts
    - high risk
  4. 5q- syndrome
    - high risk ⇒ AML
56
Q
  1. Acute myelogenous leukemia:

ACUTE MYELOID LEUKEMIA classification

A
  1. AMLs associated with specific genetic mutations
    - t(15;17) PML/RARA
    - t(8;21) CBFb/ETO
    - inv(16) CBFa/MYH11
    - t(11q23;v) MLL
  2. AMLs associated with dysplasia
  3. AMLs occurring after genotoxic chemotherapy
  4. AMLs that don’t fit to previous categories
    - M0: undiff, CD13, CD33
    - M1: weak diff. , some MPO+
    - M2: diff., Auer rods+
    - M3: acute promyelocytic leukemia
    - M4: acute myelomonocytic leukemia
    - M5: acute monocytic leukemia
    - M6: acute erythroleukemia
    - M7: acute megakaryocytic leukemia, CD61,64
57
Q
  1. Acute myelogenous leukemia:

ACUTE MYELOID LEUKEMIA pathogenesis

A
  • mutation in gene coding TF needed for normal myeloid cell differentiation
  • t(15;17) ⇒ fusion of PML to retinoic acid receptor alpha ⇒ fusion gene ⇒ blocks differentiation at promyelocytic stage
  • other mutations may help with cellular proliferation + survival
58
Q
  1. Acute myelogenous leukemia:

ACUTE MYELOID LEUKEMIA morphology + clinical features

A

MORPHOLOGY:
- myeloblasts: 3-5 nucleoli, delicate chromatin, fine azurophilic cytoplasmic granules
- auer rods= MPO clustered
- hiatus leukemikus= gap between matured + unmeasured cells
CLINICAL FEATURES:
- fatigue, pallor, abnormal bleeding, infections
- spenomegaly, lymphadenopathy
- diagnosis based on morphological, histochemical, immunophenotypical + karyotypical findings
TREATMENT:
- chemotherapy
- target therapy

59
Q
  1. Precursor T- and B-cell lymphoblastic leukemia/lymphoma:

WHO CLASSIFICATION

A
  • done by:
    • morphology
    • cell of origin
    • clinical features
    • genotype
      CATEGORIES:
      1. Tumors of B cells
    • precursor B cell neoplasms
    • peripheral B cell neoplasms
      2. Tumors of T cells
    • precursor T cell neoplasms
    • peripheral T/NK cell neoplasms
      3. Hodgkin lymphoma
60
Q
  1. Precursor T- and B-cell lymphoblastic leukemia/lymphoma:

PRECURSOR T- AND B-CELL LYMPHOBLASTIC LEUKEMIA general + pathogenesis

A
  • aggressive
  • composed of immature lymphocytes
  • mostly in children/ young adults
  • Pre-B cell tumors ⇒ bone marrow
  • Pre-T cell tumors ⇒ thymus
    PATHOGENESIS:
    • defect: block of differentiation
    • due to mutation in specific TF
    • B-ALL: TEL-1, AML 1, E2A, PAX5, EBF
    • T-ALL: TAL 1, NOTCH 1
    • B-ALL: t(9;22) philadelphia
61
Q
  1. Precursor T- and B-cell lymphoblastic leukemia/lymphoma:

PRECURSOR T- AND B-CELL LYMPHOBLASTIC LEUKEMIA clinical features + laboratory findings

A 
CLINICAL FEATURES:
  - abrupt, stormy onset
  - fatique, fever, bleeding 
  - bone pain + tenderness
  - lymphadenopathy, splenomegaly, hepatomegaly
  - CNS manifestations: headache, vomiting, nerve palsies
LABORATORY FINDINGS:
  - anemia present
  - WBC count variable
  - platelet count low
  - neutropenia
62
Q
  1. Precursor T- and B-cell lymphoblastic leukemia/lymphoma:

PRECURSOR T- AND B-CELL LYMPHOBLASTIC LEUKEMIA morphology

A
  • Lymphoblasts: coarse, clumped chromatin, 1-2 nuclei, little agranular cytoplasm
  • Myeloblasts: nuceli with finer chromatin + granular cytoplasm
  • B-ALL: hyperdiploidy + t(12;21)TEL1/AML1, t(9;22)BCR/ABL
  • T-ALL: translocations of T cell receptor loci and TAL 1 TF
63
Q
  1. CLL and hairy cell leukemia:

CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LEUKEMIA pathogenesis + morphology

A

PATHOGENESIS:
- slow growing tumor ⇒ survival more important than proliferation
- high level of BCL2 ⇒ inhibit apoptosis
- immune dysregulation: tumor suppresses normal B cell function ⇒ hypogammaglobulinemia
MORPHOLOGY:
- sheets of small lymphocytes and scattered foci of larger dividing cells
- proliferations centers in mitotically active cells
- bone marrow, spleen, liver involved
- lymphocytosis
- smudge cells
- B cell markers: CD19, 20, 23 + surface Ig chains + CD5

64
Q
  1. CLL and hairy cell leukemia:

CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LEUKEMIA clinical features

A
  • fatigue, weight loss, anorexia
  • lymphadenopathy + hepatosplenomegaly
  • leukocyte count elevated
  • hypogammaglobulinemia
  • autoimmune hemolytic anemia
  • thrombocytopenia
  • median survival ⇒ 4-6 yrs
    TREATMENT:
    • biological therapy
    • chemotherapy
    • stem cell therapy
    • bone marrow transplant
65
Q
  1. CLL and hairy cell leukemia:

HAIRY CELL LEUKEMIA

A
  • slow growing B cell tumor
  • arises in epithelial tissues: stomach, salivary glands, intestine, lungs, orbit, breast
  • leukemic cells with fine, hairlike cytoplasmic projections
  • in people with autoimmune diseases or chronic infections + older males
  • markers: CD19, CD20, CD11c, CD103
  • mutation in BRAF
    SYMPTOMS:
    • splenomegaly
    • pancytopenia
    • infections
      TREATMENT:
    • H.pylori ⇒ antibiotics + PPis
    • radiotherapy, local excision, chemotherapy
66
Q
  1. Multiple myeloma and related plasma cell disorders:

GENERAL INFO FOR PLASMA CELL TUMORS

A
  • myeloma = bone marrow tumor of plasma cells
  • monoclonal gammopathies
  • associated immunoglobulin M protein
  • middle + elderly ages
    TYPES:
    • multiple myeloma
    • solitary plasmacytoma
    • lymphoplastic lymphoma
    • heavy-chain disease
    • primary amyloidosis
    • MGUS
67
Q
  1. Multiple myeloma and related plasma cell disorders:

PATHOGENESIS OF MYELOMAS

A
  • chromosome translocation of IgH, cyclin D1, FGFR3 and cyclinD3 ⇒ dysregulation of F cyclins
  • IL-6: supports myeloma cell proliferation
  • myeloma cells produce ⇒ IL-1b, TNF and IL-6 ⇒ RANKL production ⇒ osteoclast stimulation ⇒ bone marrow resorption
    • IL-3: block osteoblast progenitor
    • DKK1: block OPG production
    • MiP1alpha: activate osteoclasts
  • myeloma patients are immunosuppressed
  • renal dysfunction
68
Q
  1. Multiple myeloma and related plasma cell disorders:

MORPHOLOGY OF MYELOMAS

A

MULTIPLE MYELOMA:
- lesions in medullary cavity ⇒ erode cancellous bone ⇒ destroy cortical bone
- increased amount of plasma cells
- infiltration of spleen, liver, kidney, lungs, LN
- myeloma nephrosis ⇒ RF due to proteinaceous casts in DCT and CD
* surrounded by multinucleated cells
* necrotic epithelial cells next to cast due to Bence Jones protein toxicity
* metastatic calcification
* AL amyloidosis
* bacterial pyelonephritis
LYMPHOPLASMACYTIC LYMPHOMA:
- no skeletal lesions
- neoplastic cells diffusely infiltrate

69
Q
  1. Multiple myeloma and related plasma cell disorders:

CLINICAL FEATURES OF MYELOMAS

A 
MULTIPLE MYELOMA:
  - bone pain
  - hypercalcemia
  - anemia
  - recurrent infections
  - renal insufficiency
  - AL amyloidosis
  - hyperviscosity symptoms
LYMPHOPLASMACYTIC LYMPHOMA:
  - age: 60-80yrs
  - Waldenström macroglobulinemia
  - visual impairment
  - neurological signs
  - bleeding
  - cryoglobulin
70
Q
  1. Multiple myeloma and related plasma cell disorders:

MULTIPLE MYELOMA

A
  • age: 70yrs
  • progressive disease, survival: 4-6yrs
  • involves bone marrow ⇒ osteolytic lesion
  • M proteins: IgG, IgA, IgM, IgD, IgE, k and lambda
  • treatment: proteasome inhibitors
71
Q
  1. Multiple myeloma and related plasma cell disorders:

SOLITARY PLASMACYTOMA

A
  • involves skeleton + soft tissues
  • progress to multiple myeloma in 5-10yrs
  • in soft tissues: rarely spread + local surgery
72
Q
  1. Multiple myeloma and related plasma cell disorders:

LYMPHOPLASMACYTIC LYMPHOMA

A
  • age: 60-70yrs
  • survival: 4-5 yrs
  • tumor cells secrete IgM
  • involves LN, BM, spleen
  • Waldenström macroglobulinema
  • treatment: chemotherapy, plasmaphoresis
73
Q
  1. Multiple myeloma and related plasma cell disorders:

HEAVY-CHAIN DISEASE

A
  • group of proliferations
  • only 1 heavy chain produced ⇒ IgA usually
  • location: small intestine, respiratory tract
  • less common IgG: lymphadenopathy, hepatosplenomegaly
74
Q
  1. Multiple myeloma and related plasma cell disorders:

MGUS

A
  • asymptomatic monoclonal gammopathy

- precursor for multiple myeloma

75
Q
  1. Follicular lymphoma, Mantle cell lymphoma, MALT lymphoma:
    FOLLICULAR LYMPHOMA general + pathogenesis
A
  • adults over 50 yrs old
  • survival: 7-9 yrs
    PATHOGENESIS:
    • express BCL2 ( t(14;18)BCL2/IgH
    • loss of function mutation for histone acetyl transferases
76
Q
  1. Follicular lymphoma, Mantle cell lymphoma, MALT lymphoma:
    FOLLICULAR LYMPHOMA morphology + clinical features
A

MORPHOLOGY:
- tumor cells ⇒ like normal GC B cells but larger than resting lymphocytes
- centrocytes ⇒ irregular outlines on nuclei
- centroblasts⇒ prominent nuclei + larger
- no single necrotic cells
- follicular hyperplasia
- markers: CD19, 20, 10, BCL6, TF
CLINICAL FEATURES:
- painless, generalized lymphadenopathy
- stays to bone marrow
- therapy: cytotoxic drugs + rituximab

77
Q
  1. Follicular lymphoma, Mantle cell lymphoma, MALT lymphoma:
    MANTLE CELL LYMPHOMA general + pathogenesis
A
  • cells looking like naive B cells found in mantle zones of normal follicles
  • men over 50 yrs old
  • survival: 3-5yrs
    PATHOGENESIS:
    • t(11;14) ⇒ dysregulates cyclin D1 ⇒ uncontrolled growth
    • tumor cells coexpress IgM and IgD, CD19,20,5
    • no proliferation centers
    • cyclin D1 protein
78
Q
  1. Follicular lymphoma, Mantle cell lymphoma, MALT lymphoma:
    MANTLE CELL LYMPHOMA morphology + clinical features
A 
MORPHOLOGY:
  - LN involved in diffuse pattern
  - tumor cells larger than normal lymphocytes, irregular nucleus, no nucleoli, scant cytoplasm
  - BM involved + peripheral blood
CLINICAL FEATURES:
  - fatigue, lymphadenopathy
  - BM, spleen, liver, GI involved
  - moderately aggressive + incurable
79
Q
  1. Follicular lymphoma, Mantle cell lymphoma, MALT lymphoma:
    MALT LYMPHOMA
A
  • low-grade mature B cell tumor in MALT tissue
  • develop in setting of autoimmune disease or chronic infection
  • T(11;18) MALT1/IAP2 gene abnormalities
    PATHOGENESIS:
    • H.pylori infection ⇒ chronic gastritis ⇒ gastric atrophy ⇒ activate B and T cells ⇒ proliferation of lymphoid cells ⇒ mutations ⇒ MALT lymphoma
      TREATMENT:
    • local excision
    • radiotherapy
80
Q
  1. Diffuse large B-cell lymphoma, Burkitt lymphoma:

DIFFUSE LARGE B-CELL LYMPHOMA pathogenesis + subtypes

A

PATHOGENESIS:
- BCL6 gene rearrangement (3q27)
- point mutation in BCL6 promoter ⇒ increase protein ⇒ transcriptional regulator of gene expression in GC B cells
- t(14;18) ⇒ BCL2 overexpression
- loss of function mutation for histone acetyl transferases
SUBTYPES:
1. EBV associated DLBCL
- in people with AIDS, immunosuppression or elderly
- EBV driven polyclonal B cell proliferation ⇒ transform into clonal large B cell lymphoma
2. Kaposi sarcoma herpesvirus
- in pleural cavity, pericardium, peritoneum
3. Mediastinal large B cell lymphoma
- in young women
- spread to abdominal viscera + CNS

81
Q
  1. Diffuse large B-cell lymphoma, Burkitt lymphoma:

DIFFUSE LARGE B-CELL LYMPHOMA, BURKITT LYMPHOMA morphology + clinical features

A

MORPHOLOGY:
- Neoplastic B cells: large + vary in appearance
CLINICAL FEATURES:
- age: 60yrs
- fast enlarging mass, often extra nodal
- aggressive + fatal
- treatment: chemotherapy + antiCD20 immunotherapy

82
Q
  1. Diffuse large B-cell lymphoma, Burkitt lymphoma:

BURKITT LYMPHOMA pathogenesis

A
  • translocation involving MYC gene (chr.8). T(8;14) MYC/IgH ⇒ dysregulation + overexpression of MYC protein ⇒ proliferation
  • latent tumor cell infection of EBV
83
Q
  1. Diffuse large B-cell lymphoma, Burkitt lymphoma:

BURKITT LYMPHOMA morphology

A
  • tumor cells are intermediate size
  • round-oval nuclei, 2-5 nucleoli
  • cytoplasm basophilic + filled with small vacuoles
  • high rate of proliferation + apoptosis ⇒ many macrophages present ⇒ clear space ⇒ starry sky pattern
84
Q
  1. Diffuse large B-cell lymphoma, Burkitt lymphoma:

BURKITT LYMPHOMA clinical features

A
  • arises extranodal
  • diffuse involvement of LN
    TYPES:
    1. endemic:
    • children 5 yrs
    • maxillary or mandibular tumor
    • EBV associated ⇒ connected with malaria
    • grows rapidly
      2. Non-endemic:
    • in LN, GI, retroperitoneum
      3. Post-transplant:
    • EBV related
    • need lifetime immunosuppression for transplant
      TREATMENT: chemotherapy
85
Q
  1. Mature T-cell and NK-cell lymphomas:

SÉZARY SYNDROME

A
  • cutaneous T cell lymphoma
  • generalized exfoliative erythroderma
  • tumor cells in peripheral blood
86
Q
  1. Mature T-cell and NK-cell lymphomas:

MYCOSIS FUNGOIDES

A
  • cutaneous T cell lymphoma
  • nonsprecific rash ⇒ plaque ⇒ tumor
  • infiltration of epidermis + upper dermis by neoplastic mature T cells, have cerebriform nucleus
  • with progression nodal and visceral dissemination appear
87
Q
  1. Mature T-cell and NK-cell lymphomas:

ADULT T-CELL LEUKEMIA/LYMPHOMA

A 
- cause: HTLV-1
MORPHOLOGY:
  - lymphoid malignancy
  - transverse myelitis: demyelination in spinal cord
  - skin lesions
  - lymphadenopathy
  - hepatosplenomegaly
  - hypercalcemia
- very aggressive
- survival: 8 months
88
Q
  1. Hodgkin Lymphoma:

HODGKIN LYMPHOMA classification

A
  1. Nodular sclerosis
  2. Mixed cellularity
  3. Lymphocyte rich
  4. Lymphocyte depletion
  5. Lymphocyte predominance
89
Q
  1. Hodgkin Lymphoma:

RED-STERNBERG CELL

A
  • very large (15-45 microm)
  • large multilobar nucleus ⇒ mirror-image lobes
  • prominent nucleoli
  • eosinophilic cytoplasm
  • express CD15, CD30
  • atypical cell + granulomatous microenvironment
90
Q
  1. Hodgkin Lymphoma:

NODULAR SCLEROSIS HODGKIN LYMPHOMA

A
  • in teenagers + young adults
  • location: lower cervical, supraclavicular or mediastinal LN
  • good prognosis
  • lacunar cells
  • collagen bands divide lymph tissue into nodules
  • cell infiltrate
91
Q
  1. Hodgkin Lymphoma:

MIXED CELLULARITY HODGKIN LYMPHOMA

A
  • age: >50yrs
  • male predominance
  • classic RS seen
  • often disseminated + associated with systemic changes
92
Q
  1. Hodgkin Lymphoma:

LYMPHOCYTE-PREDOMINANCE HODGKIN LYMPHOMA

A
  • lymphohistiocytic variant RS cells ⇒ popcorn cell in large nodules
  • rarely other reactive cells
  • isolated cervical or axillary lymphadenopathy
  • good prognosis
93
Q
  1. Hodgkin Lymphoma:

PATHOGENESIS

A
  • arise from GC B cells
  • EBV present in RS cells in 70% of mixed-cellularity HL
  • inflammatory cell infiltrate : RS secrete IL-5, TGFb, IL-13
94
Q
  1. Hodgkin Lymphoma:

STAGING + CLINICAL FEATURES

A 
- painless lymphadenopathy
ANN ARBOR CLASSIFICATION:
 1. 1 LN or 1 extralymphatic organ
 2. 2< LN on same side of diaphragm
 3. both sides of diaphragm
 4. multiple or disseminated foci of one or more extra lymphatic organs
SYMPTOMS:
 - fever, night sweat, weight loss, pruritus, anemia
95
Q
  1. Hodgkin Lymphoma:

HODGKIN VS NON-HODGKIN LYMPHOMA

A

HODGKIN LYMPHOMA:
- localized to single axial group of nodes
- orderly spread by contiguity
- mesenteric nodes + Waldeyer ring rarely involved
- extranodal involvement uncommon
NON-HODGKIN LYMPHOMA:
- multiple peripheral nodes
- noncontiguous spread
- mesenteric nodes + Waldeyer ring involved
- extranodal involvement common

PATHOLOGY 2 (11 decks)

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