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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
18. Non-neoplastic disorders of myeloid and lymphoid systems: LEUKOPENIA morphology + clinical features
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
26
18. Non-neoplastic disorders of myeloid and lymphoid systems: REACTIVE LEUKOCYTOSIS classification
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
27
18. Non-neoplastic disorders of myeloid and lymphoid systems: INFECTIOUS MONONUCLEOSIS pathogenesis
- Epstein-Barr virus - transmitted through oral contact - infect oropharynx ⇒ LN ⇒ infects mature B cells ⇒ polyclonal activation + proliferation ⇒ secrete AB - virus specific CD8+ T cells
28
18. Non-neoplastic disorders of myeloid and lymphoid systems: INFECTIOUS MONONUCLEOSIS morphology + clinical features
``` 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 ```
29
18. Non-neoplastic disorders of myeloid and lymphoid systems: ACUTE NON-SPECIFIC REACTIVE LYMPHADENITIS
- inflamed nodes swollen, grey-red + large germinal centers - overlying skin red - infiltrative neutrophils - severe infection ⇒ follicular centers necrotize
30
18. Non-neoplastic disorders of myeloid and lymphoid systems: CHRONIC NON-SPECIFIC LYMPHADENITIS
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
31
18. Non-neoplastic disorders of myeloid and lymphoid systems: CAT-SCRATCH DISEASE
- self-limited lymphadenitis - cause: Bartonella henselae SYMPTOMS: - regional lymphadenopathy - encephalitis - osteomyelitis - thrombocytopenia MORPHOLOGY: - sarcoid like granulomas ⇒ central necrosis ⇒ abscess - follicles preserved TREATMENT: antibiotics
32
18. Non-neoplastic disorders of myeloid and lymphoid systems: TOXOPLASMA LYMPHADENITIS
- cause: Toxoplasma gondii - small proliferations ⇒ epitheloid cell clusters - asymptomic / flu-like symptoms
33
19. CML and chronic myelofibrosis: | CHRONIC MYELOGENOUS LEUKEMIA pathogenesis
- affects adults 25-60yrs - BCR-ABL fusion gene⇒ translocation (9;22) philadelphia - lineage: granulocytic, erythroid, megakaryocytic and B cell precursors
34
19. CML and chronic myelofibrosis: | CHRONIC MYELOGENOUS LEUKEMIA morphology
- 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
35
19. CML and chronic myelofibrosis: | CHRONIC MYELOGENOUS LEUKEMIA clinical features
- 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
36
19. CML and chronic myelofibrosis: | CHRONIC MYELOGENOUS LEUKEMIA therapy
- chemotherapy ⇒ decreased WBC count - gene targeted therapies (Gleeve = imatinib mesylate) - resistant disease ⇒ hematopoietic stem cell transplantation
37
19. CML and chronic myelofibrosis: | PRIMARY MYELOID FIBROSIS pathogenesis
- 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
38
19. CML and chronic myelofibrosis: | PRIMARY MYELOID FIBROSIS morphology
- peripheral blood smear: * poikilocytes (tear drop RBCs) * leukoerythroblastosis (nucleated erythroid precursors) * large platelets - extramedullar hematopoiesis - splenomegaly - hepatomegaly - hypocellular + fibrotic bone marrow
39
19. CML and chronic myelofibrosis: | PRIMARY MYELOID FIBROSIS clinical features
- anemia + thrombocytopenia - hyperuricemia + gout - thrombotic + hemorrhagic episoides (eccymoses) - splenic infarctions - survival 4-5yrs TREATMENT: - chemotherapy - stem cell transplant - transfusion - splenectomy
40
20. Polycythemia vera, Essential thrombocythemia: | ESSENTIAL THROMBOCYTHEMIA
- 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
20. Polycythemia vera, Essential thrombocythemia: | POLYCYTHEMIA VERA pathogenesis
- 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
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20. Polycythemia vera, Essential thrombocythemia: | POLYCYTHEMIA VERA morphology
``` - increased blood volume + viscosity ⇒ congestion ⇒ hepatomegaly ⇒ splenomegaly ⇒ thrombosis + infarctions ⇒ hemorrhages ⇒ hypercellular bone marrow ⇒ Trousseau's phenomenon ```
43
20. Polycythemia vera, Essential thrombocythemia: | POLYCYTHEMIA VERA clinical features + diagnosis
- 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
21. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen: SPLENOMEGALY consequences
- anemia, leukopenia, thrombocytopenia - hypersplenism - platelets susceptible to sequestration in red pulp ⇒ increased thrombocytopenia - rupture
45
21. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen: MASSIVE SPLENOMEGALY
- myeloproliferative disorders - chronic lymphocytic leukemia - hairy cell leukemia - lymphomas - malaria - Gaucher disease - primary tumors of spleen
46
21. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen: MODERATE SPLENOMEGALY
- chronic congestion - acute leukemias - hereditary spherocytosis - thalassemia major - autoimmune hemolytic anemia - amyloidosis - Niemann-Pick disease - chronic splenitis - TB, sarcoidosis, typhoid - metastatic carcinoma/ sarcoma
47
21. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen: MILD SPLENOMEGALY
- acute splenitis - acute splenic congestion - infectious mononucleosis - miscellaneous disorders ⇒ septicemia, SLE, intra-abdominal infections
48
21. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen: HYPERSPLENISM
= 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
21. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen: RUPTURED SPLEEN
- 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
21. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen: SPLENECTOMY
- done when there is traumatic rupture - no side affects - elevated risk of infections - Howell-Jolly bodies!
51
21. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen: THYMIC HYPERPLASIA
- 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
21. Disorders that affect the spleen and thymus/ 31. Disorders that affect the spleen: THYOMA
``` = 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
22. Myelodysplastic syndromes: | MDS general + pathogenesis
``` - 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
22. Myelodysplastic syndromes: | MDS morphology + clinical features
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
22. Myelodysplastic syndromes: | OTHER DISEASES
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
23. Acute myelogenous leukemia: | ACUTE MYELOID LEUKEMIA classification
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
23. Acute myelogenous leukemia: | ACUTE MYELOID LEUKEMIA pathogenesis
- 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
23. Acute myelogenous leukemia: | ACUTE MYELOID LEUKEMIA morphology + clinical features
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
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24. Precursor T- and B-cell lymphoblastic leukemia/lymphoma: | WHO CLASSIFICATION
- 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
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24. Precursor T- and B-cell lymphoblastic leukemia/lymphoma: | PRECURSOR T- AND B-CELL LYMPHOBLASTIC LEUKEMIA general + pathogenesis
- 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
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24. Precursor T- and B-cell lymphoblastic leukemia/lymphoma: | PRECURSOR T- AND B-CELL LYMPHOBLASTIC LEUKEMIA clinical features + laboratory findings
``` 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 ```
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24. Precursor T- and B-cell lymphoblastic leukemia/lymphoma: | PRECURSOR T- AND B-CELL LYMPHOBLASTIC LEUKEMIA morphology
- 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
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25. CLL and hairy cell leukemia: | CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LEUKEMIA pathogenesis + morphology
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
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25. CLL and hairy cell leukemia: | CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LEUKEMIA clinical features
- 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
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25. CLL and hairy cell leukemia: | HAIRY CELL LEUKEMIA
- 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
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26. Multiple myeloma and related plasma cell disorders: | GENERAL INFO FOR PLASMA CELL TUMORS
- 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
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26. Multiple myeloma and related plasma cell disorders: | PATHOGENESIS OF MYELOMAS
- 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
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26. Multiple myeloma and related plasma cell disorders: | MORPHOLOGY OF MYELOMAS
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
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26. Multiple myeloma and related plasma cell disorders: | CLINICAL FEATURES OF MYELOMAS
``` 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 ```
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26. Multiple myeloma and related plasma cell disorders: | MULTIPLE MYELOMA
- 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
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26. Multiple myeloma and related plasma cell disorders: | SOLITARY PLASMACYTOMA
- involves skeleton + soft tissues - progress to multiple myeloma in 5-10yrs - in soft tissues: rarely spread + local surgery
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26. Multiple myeloma and related plasma cell disorders: | LYMPHOPLASMACYTIC LYMPHOMA
- age: 60-70yrs - survival: 4-5 yrs - tumor cells secrete IgM - involves LN, BM, spleen - Waldenström macroglobulinema - treatment: chemotherapy, plasmaphoresis
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26. Multiple myeloma and related plasma cell disorders: | HEAVY-CHAIN DISEASE
- group of proliferations - only 1 heavy chain produced ⇒ IgA usually - location: small intestine, respiratory tract - less common IgG: lymphadenopathy, hepatosplenomegaly
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26. Multiple myeloma and related plasma cell disorders: | MGUS
- asymptomatic monoclonal gammopathy | - precursor for multiple myeloma
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27. Follicular lymphoma, Mantle cell lymphoma, MALT lymphoma: FOLLICULAR LYMPHOMA general + pathogenesis
- 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
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27. Follicular lymphoma, Mantle cell lymphoma, MALT lymphoma: FOLLICULAR LYMPHOMA morphology + clinical features
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
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27. Follicular lymphoma, Mantle cell lymphoma, MALT lymphoma: MANTLE CELL LYMPHOMA general + pathogenesis
- 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
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27. Follicular lymphoma, Mantle cell lymphoma, MALT lymphoma: MANTLE CELL LYMPHOMA morphology + clinical features
``` 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 ```
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27. Follicular lymphoma, Mantle cell lymphoma, MALT lymphoma: MALT LYMPHOMA
- 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
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28. Diffuse large B-cell lymphoma, Burkitt lymphoma: | DIFFUSE LARGE B-CELL LYMPHOMA pathogenesis + subtypes
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
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28. Diffuse large B-cell lymphoma, Burkitt lymphoma: | DIFFUSE LARGE B-CELL LYMPHOMA, BURKITT LYMPHOMA morphology + clinical features
MORPHOLOGY: - Neoplastic B cells: large + vary in appearance CLINICAL FEATURES: - age: 60yrs - fast enlarging mass, often extra nodal - aggressive + fatal - treatment: chemotherapy + antiCD20 immunotherapy
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28. Diffuse large B-cell lymphoma, Burkitt lymphoma: | BURKITT LYMPHOMA pathogenesis
- translocation involving MYC gene (chr.8). T(8;14) MYC/IgH ⇒ dysregulation + overexpression of MYC protein ⇒ proliferation - latent tumor cell infection of EBV
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28. Diffuse large B-cell lymphoma, Burkitt lymphoma: | BURKITT LYMPHOMA morphology
- 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
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28. Diffuse large B-cell lymphoma, Burkitt lymphoma: | BURKITT LYMPHOMA clinical features
- 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
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29. Mature T-cell and NK-cell lymphomas: | SÉZARY SYNDROME
- cutaneous T cell lymphoma - generalized exfoliative erythroderma - tumor cells in peripheral blood
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29. Mature T-cell and NK-cell lymphomas: | MYCOSIS FUNGOIDES
- 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
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29. Mature T-cell and NK-cell lymphomas: | ADULT T-CELL LEUKEMIA/LYMPHOMA
``` - cause: HTLV-1 MORPHOLOGY: - lymphoid malignancy - transverse myelitis: demyelination in spinal cord - skin lesions - lymphadenopathy - hepatosplenomegaly - hypercalcemia - very aggressive - survival: 8 months ```
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30. Hodgkin Lymphoma: | HODGKIN LYMPHOMA classification
1. Nodular sclerosis 2. Mixed cellularity 3. Lymphocyte rich 4. Lymphocyte depletion 5. Lymphocyte predominance
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30. Hodgkin Lymphoma: | RED-STERNBERG CELL
- very large (15-45 microm) - large multilobar nucleus ⇒ mirror-image lobes - prominent nucleoli - eosinophilic cytoplasm - express CD15, CD30 - atypical cell + granulomatous microenvironment
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30. Hodgkin Lymphoma: | NODULAR SCLEROSIS HODGKIN LYMPHOMA
- in teenagers + young adults - location: lower cervical, supraclavicular or mediastinal LN - good prognosis - lacunar cells - collagen bands divide lymph tissue into nodules - cell infiltrate
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30. Hodgkin Lymphoma: | MIXED CELLULARITY HODGKIN LYMPHOMA
- age: >50yrs - male predominance - classic RS seen - often disseminated + associated with systemic changes
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30. Hodgkin Lymphoma: | LYMPHOCYTE-PREDOMINANCE HODGKIN LYMPHOMA
- lymphohistiocytic variant RS cells ⇒ popcorn cell in large nodules - rarely other reactive cells - isolated cervical or axillary lymphadenopathy - good prognosis
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30. Hodgkin Lymphoma: | PATHOGENESIS
- 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
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30. Hodgkin Lymphoma: | STAGING + CLINICAL FEATURES
``` - 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 ```
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30. Hodgkin Lymphoma: | HODGKIN VS NON-HODGKIN LYMPHOMA
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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