Hematopathology Flashcards
RBC Life Cycle/ Structure
- EPO → normoblasts → loss of nucleus → reticulocytes → mature RBC
- Reticulocyte stage: 5-7 days
- RBC life span: 120 days
RBC Parameters (4)
• Mean Cell Volume (MCV): average volume of an RBC • Mean Cell Hemoglobin (MCH): average content of Hb per RBC • Mean Cell Hemoglobin Concentration (MCHC): average concentration of Hb in a given volume of RBC’s • Red Cell Distribution Width (RDW): coefficient of variation of RBC volume
Hemolytic Anemias
ETIOLOGY:
- Intravascular Hemolysis: mechanical injury to RBC
- Defective cardiac valves
- Microvascular thrombi
- Complement Fixation
- Infections (malaria, clostridia toxin)
- Extravascular Hemolysis: RBC rendered deformed or foreign
- Spherocytosis
- Sickle Cell anemia
- Immune antibody coating
PATHOGENESIS: shortened RBC life span - increased erythropoietin and erythropoiesis
- Intrinsic RBC Defect: membrane defect (spherocytosis), enzyme defect (G6PD), hemoglobin defect( Sickle cell and Thalassemias)
- Extrinsic RBC Defect: Immune mediated damage, trauma, infections Acute Hemorrhage - hypovolemia chronic Hemorrhage - iron stored becomes depleted
MORPHOLOGY:
- normochromic, normocytic anemia
- Polychromasia
- Erythroid hyperplasia
- Increased bilirubin, hemoglobin, and LDH
- Decreased Haptoglobin
Hereditary Spherocytosis
ETIOLOGY: mutated proteins in the RBC membrane skeleton
- Northern Europeans
- Autosomal dominant
MORPHOLOGY: RBCs become spheroid and rigid
• With splenectomy → Howell-Jolly Bodies (DNA remains left due to splenectomies)
PATHOGENESIS: reduced RBC membrane stability → 10-20 day life span
- Ankyrin
- Band 3
- Spectrin
- Band 4.2
- Reduced RBC membrane stability → loss of small fragments during normal shearing stresses in the blood circulation → RBCs become increasingly more spherical → unable to traverse the splenic sinusoids → phagocytosis and destruction by splenic macrophages (spleen usually enlarged)
SYMPTOMS: chronic hemolytic anemia, gall stones (increased bilirubin)
- TREATMENT: splenectomy → anemia corrects, spherocytosis persists
- DIAGNOSIS:
- Osmotic Fragility Test: when exposed to hypotonic salt solutions → RBCs lyse prematurely
- Increased MCHC (only one)
- Increased LDH
G6PD Deficiency
- ETIOLOGY: abnormality in the Hexose Monophosphate Shunt due to impaired enzyme function - leaves RBC’s prone to oxidative injury
- X-linked recessive
- G6PD Type B = most common
- African Americans (Type A)
- Mediterranean/Middle Eastern (Type B)
- PATHOGENESIS: exposure to oxidants (abnormal protein folding and increased proteolytic degradation) → oxidation of SH groups on globin chains → precipitation of denatured globins = Heinz bodies
- severe damage → RBC to spleen → macrophage bite out inclusions → bite cells → extravascular hemolysis
- Presentation follows infection, Sulfa drugs, fava beans
- SYMPTOMS:
- Acute hemolysis
- Neonatal jaundice (uncommon)
- Heterozygote advantage against P. falciparum malaria
Sickle Cell Disease (HbS)
- ETIOLOGY: point mutation at position 6 in B-globin chain (glutamic acid → valine)
- 10% of African Americans are HbAS (heterozygotes)
PATHOGENESIS: HbS aggregate during crises (sticky) - formation of long-needle like structures
SICKLING FACTORS:
- Amount of HbS & its interaction with other Hb chains in the red cell:
- HbA & HbF decrease sickling; HbC sickling increased. - Hb concentration per red cell: Dehydration increased sickling Coexisting α-thalassemia decreases sickling (less globin, therefore less hemoglobin). - Acidity: lower pH increases sickling. -Length of exposure to low O2 tension.
CRISIS
- Vaso-occlusive/ painful crises: ischemic events due to microvascular occlusions
- Sequestration crises: rapid pooling of blood in the spleen.
- Aplastic crises: acute viral infection, due to parvovirus B19 (infects red cell precursors).
- Hemolytic crises.
MORPHOLOGY: target cells
SYMPTOMS:
- Chronic hemolysis (intravascular & extravascular)
- Hyperplastic bone marrow → skull bone changes in kids
- Repeated infarction and fibrosis → Autosplenectomy in children → susceptible to H. influenzae and Pneumococcus
- Jaundice
- Microvascular occlusions
- Osteomyelitis with Salmonella infections
- Aplastic crises: acute viral infection (Parvo B19)
DIAGNOSIS: mixing blood with O2 consuming agent induces sickling
• Hemoglobin electrophoresis
TREATMENT: analgesics, B9, Hydroxyurea (increases HbF)
B-Thalassemias
- ETIOLOGY: diminished synthesis of structurally normal B-globin chains (chromosome 11), with unimpaired alpha-chain production
- B+ Thalassemia: reduced B chains produced (mutation in promoter)
- B(o) Thalassemia: no B chains (mutation in splicing or chain termination) •
PATHOGENESIS: reduced survival of RBCs due to cell membrane damage by precipitated alpha-chains → ineffective erythropoiesis
- 75% of RBC precursors die in bone marrow
- Excessive iron absorption
- MORPHOLOGY: hypochromic, microcytic anemia
- Target cells
- TREATMENT: bone marrow transplants
B-Thalassemia Major Syndrome
- ETIOLOGY: presents 6-9 months after birth when HbF levels naturally fall
- Mediterranean, Africa, SE Asia
- PATHOGENESIS: B+/B+, B+/B(o), B(o)/B(o) = severe transfusion-dependent anemia
SYMPTOMS: • Expansion of hematopoietic marrow → prominent facial bones, erosion of bony cortex, new bone formation
- Hepatosplenomegaly → due to extravascular hemolysis
- Hemosiderosis
- Secondary hemochromatosis due to iron overload → cardiac failure, liver failure, pancreatic damage - growth retardation + death → unless given blood transfusion
DIAGNOSIS: • Hb levels = 3-6 g/dL
• HbF remains elevated
TREATMENT: iron chelator to prevent iron overload
B-Thalassemia Minor
• PATHOGENESIS: B+/B or B(o)/B = mild hypochromic, microcytic anemia
SYMPTOMS: usually asymptomatic
• DIAGNOSIS: hemoglobin electrophoresis: increased HbA2 with normal or elevated HbF
TREATMENT: avoid treating as iron-deficiency anemia
A-Thalassemia
- Silent Carrier: one alpha-gene deleted
- A-Thalassemia Trait: 2 genes deleted
- a/a, -/- (SE Asian)
- a/-, a/- (African)
- Hemoglobin H Disease: 3 genes deleted
- HbH is formed from tetramers of excess B-chains → high affinity for O2 → hypoxia
- HbH oxidation →precipitated inclusions in RBCs → spleen → extravascular hemolysis
- Hydrops Fetalis: all 4 genes deleted (incompatible with life)
- Hb Barts formed from tetramers of excess gamma-chains → high affinity for O2 → no O2 reaches the tissues → death unless given intrauterine transfusion
Paroxysmal Nocturnal Hemoglobinuria (PNH)
- ETIOLOGY: rare acquired clonal stem cell disorder associated with periodic hemolysis
- X-linked
- Phosphatidylinositol glycan class A (PIGA)
PATHOGENESIS: PIGA gene synthesizesglycosylphosphatidyl inositol (GPI)
- GPI (anchors CD55/CD59) inhibits complement activation on blood cells
- At night → hypoventilation → decreased pH → complement activated
- PNH is rare → PIGA clones gain selective advantage to produce disease
SYMPTOMS: intravascular hemolysis, pro-thrombotic state (40% develop venous thrombosis)
- Hemoglobinuria, hemosiderinuria
- Iron deficiency
- Aplastic anemia
- 5-10% develop AML or Myelodysplastic Syndrome
DIAGNOSIS:
- Sucrose hemolysis test (screening)
- Ham’s Acid hemolysis test
- Flow Cytometry: absence of CD55 and CD59 on WBC’s
- Flaer Test
TREATMENT: Immunosuppression
Warm Antibody Immunohemolytic Anemia
- ETIOLOGY: most common form of IHA
- 50% are idiopathic
- 50% have predisposing autoimmune disease, lymphoma or drug reactions • Most antibodies are IgG
Cold Antibody Immunohemolytic Anemia
- ETIOLOGY: IgM antibodies bind and agglutinate RBCs at <4C SYMPTOMS: • Acute Self-limiting Hemolysis: seen in infectious diseases (CMV, HIV, Influenza, Mycoplasma pneumonia)
- Chronic Hemolysis: idiopathic or associated with lymphoma
Direct Antiglobulin Test (DAT):
Detection of antibodies ± complement on patient RBCs. Patient RBCs are incubated with antibodies to these elements → RBC agglutination - anti- antibodies → bind to patient RBC’s
Indirect Antiglobulin Test (IDAT):
- Patient serum is tested for its ability to agglutinate test RBCs that have known antibodies bound onto them. -Temperature dependence defines “warm” or “cold”.
Megaloblastic Anemias
- ETIOLOGY: deficiency of Vitamin B12 (cobalamine) or B9 (folate)
- Poor people, pregnant women, alcoholics, overcooked food, impaired absorption
PATHOGENESIS: both vitamins are coenzymes required for synthesis of thymidine (methionine synthase, thymidylate synthase)
- B9 → Impaired DNA synthesis → ineffective erythropoiesis → destruction of macrocytes
- B12 → Autoantibodies → Blocked IF (parietal cells) → B12 def. → Megaloblastic anemia
- MMA requires cobalamin. B12 deficiency increases urine methyl malonic acid -Neurological deficits → dorsal and lateral tracts affected: sensory and functional functions affected
- MORPHOLOGY: pancytopenia with macrocytic anemia
- (MCV>100)
- Decreased reticulocyte count
- Enlarged hyper-segmented neutrophils (5+ lobes)
- Hypercellular bone marrow
- Increased homocysteine
SYMPTOMS: Fatigue, atrophic glossitis, cheoilsosis
• Neurological symptoms → B12 ONLY → Decreased vibration/proprioception, degeneration of dorsal/lateral tracts of CNS
Pernicious Anemia
• Type II Hypersensitivity
ETIOLOGY:
- Decreased intake (diet deficient → strict vegetarian)
- Impaired GI absorption → pernicious anemia, malabsorption (IF defect)
- Common in N. Europeans, ages 40-80
PATHOGENESIS: autoimmune atrophic gastritis → failure of IF production → B12 not absorbed → B12 deficiency → Megaloblastic anemia
- SYMPTOMS: CNS deficits → sensory ataxia, lower limb parasthesia
- Atrophic gastritis
- DIAGNOSIS:
- Increased plasma and urine methyl-malonic acid
- Increased serum homocysteine
- Increased MCV
- Decreased reticulocytes
- Schilling Test: inability to absorb oral B12
- Reticulocyte Response: improvement of anemia 5 days after paraenteral B12 injections
- serum antibodies to intrinsic factor
Folate Deficiency
- ETIOLOGY:
- Decreased intake: inadequate intake of green vegetables (alcoholics)
- Impaired GI absorption
- Increased requirements (pregnancy, infancy, cancer therapy)
SYMPTOMS: no CNS symptoms DIAGNOSIS:
- Increased homocysteine
- Decreased serum folate (differentiation b/w B12 deficiency)
Iron Deficiency Anemia
• Microcytic hypochromic anemia
ETIOLOGY: most common cause of anemia worldwide
- Dietary deficiency
- Impaired absorption ( normally absorbed in the duodenum)
- Increased requirements: growing infants, premenopausal female, pregnancy
- Chronic blood loss (most commonly due to chronic GI blood loss)
DIAGNOSIS:
- CBC: decreased Hb, decreased MCV, increased RDW
- Blood Smear: hypochromic microcytic anemia, sometimes poikilocytosis (pencil cells)
- Biochemical: decreased transferrin saturation, increased TIBC, decreased ferritin
- Depletion of BM iron stores: Prussian Blue stain of bone marrow is negative
NORMAL METABOLISM: mostly absorbed in the duodenum
- Hepcidin: inhibits ion uptake from duodenal mucosal cells in response to high levels of iron stores
- Free iron is toxic → Fe is bound as ferritin
- Storage: ferritin (in liver, spleen, BM, muscle) + hemosiderin
- Transport: transferrin
- Functional iron → 80% is bound to hemoglobin
SYMPTOMS: Koilonychia, decreased reticulocytes, MCV, MCHC
- Plummer Vinson Syndrome = Iron deficiency anemia, proximal esophageal webs, atrophic glossitis
- Pica Syndrome = Eat dirt, ice (psychiatric problems)
Anemia of Chronic Disease
- ETIOLOGY:
- Chronic bacterial infections: lung abscesses, endocarditis, tuberculosis
- Chronic immune disorders: rheumatoid arthritis
- Malignant tumors: lung, breast, lymphoma
PATHOGENESIS: impaired iron utilization and decreased RBC production
- Increased Hepcidin → decreased transfer of iron from bone marrow pool to RBC precursors due to inflammatory mediators
- Decreased erythropoiesis with low EPO
- MORPHOLOGY: hypochromic, microcytic anemia
DIAGNOSIS: decreased serum Fe, decreased TIBC (transferritin) , increased ferritin
Aplastic Anemia
- ETIOLOGY: pancytopenia → bone marrow failure due to defect in multi-potent hematopoietic stem cell
- Congenital/Hereditary (Fanconi anemia)
- Myelophthisic Anemia: bone marrow replaced by abnormal infiltrates (granulomas)
- Chronic Renal Disease: decreased EPO
- Acquired:
- Idiopathic (65%) - immune mediated destruction of altered stem cells -primary intrinsic stem cell defect
- Chemical Agents (35%) → chemotherapy, chloraphenicol, chloropromazine, phenytoin
- Viral: CMV, EBV, VZV
- PATHOGENESIS: bone marrow failure due to auto-reactive T cell defect in a multipotent hematopoietic stem cell
COMPLICATIONS: recurrent infections
DIAGNOSIS: low reticulocyte count
• BM Biopsy: hypocellular, often only fat cells, stroma and scattered lymphocytes
Infectious Mononucleosis
- ETIOLOGY: Patients with EBV “kissing disease”
- PATHOGENESIS: Infects B cells in the oropharyngeal epithelium → B cells spread infection → T lymphocyte response is essential to control, but is ineffective
MORPHOLOGY: Atypical lymphocytes: Downey cells
• RBC’s pushing into the cytoplasm (ballerina skirt appearance)
SYMPTOMS: Fatigue, sore throat, fever, lymphadenopathy
• Atypical: Hepatitis, febrile rash, hepatosplenomegaly
COMPLICATIONS: Splenic rupture → hypovolemic shock
• Non-Hodgkin B cell lymphoma
Polycythemia
• ETIOLOGY: abnormally elevated RBC concentration and Hb levels
PATHOGENESIS:
- Relative Polycythemia: due to reduced plasma volume (secondary to dehydration)
- Absolute Polycythemia:
- Primary: JAK2 mutation → Polycythemia Vera (PRV) → chronic myeloproliferative neoplasm (low EPO)
- Secondary: appropriately high EPO levels (lung disease, cyanotic heart disease, living at high altitude) or inappropriately high EPO levels (EPO secreting tumors of kidney)
Thrombocytopenia
- Decreased production
- Generalized bone marrow disease
- Aplastic anemia
- Marrow infiltration (leukemias, metastasis, granulomas)
- Drug-induced (ethanol)
- HIV
- Megaloblastic anemia
- Myelodysplastic syndromes
- Decreased survival
- Immune Destruction: antiplatelet antibodies or immune complexes (ITP, SLE)
- Drug associated: heparin, septrin, quinidine
- Non-immune: DIC, TTP/HUS, mechanical destruction, Giant hemongiomas, Microangiopathic hemolytic anemias
CAUSES - decreased platelet production - decreased platelet survival sequestration ( splenic) -dilutional
- INVESTIGATIONS: ↓Platelet count, ↑BT, Normal PT, PTT
- SYMPTOMS: Excessive bleeding, petechiae, ecchymosis, epistaxis, mucosal bleeding, CNS
Primary Immune Thrombocytopenia (ITP)
- Acute: children, post-viral with abrupt on set and spontaneous resolution
- Chronic: more common, women 20-40 with mucosal bleeding
- DIAGNOSIS: decreased, but large platelets
- Increased bleeding time
- Autoantibodies against platelet membrane glycoproteins
- Increased megakaryocytes in BM biopsy
- TREATMENT: splenectomy
Non-Immune Thrombocytopenias (TTP/HUS)
- Thrombotic Thrombocytopenic Purpura: clinical syndrome of fever, thrombocytopenia, micro-angiopathic hemolytic anemia neurological defects (ADULTS) + Renal Failure
- Hemolytic Uremic Syndrome: clinically like TTP but no neurological deficits but prominent renal failure (CHILDREN)
- In common:
- Platelet thrombi → small vessels occlusion + mechanical microangiopathic hemolytic anemia
- Platelet consumption → thrombocytopenia
Von Willebrand Disease
- ETIOLOGY: commonest inherited disorder of bleeding. Defect in platelet-to-collagen adhesion
- Type 1 (70%): reduced quantity of VWF → mostly mucosal bleeding
- Type 2 (25%): qualitative (functional) defect in VWF - mild to moderate bleeding
- Type 3 (5%): severe deficiency of VWF → patient may present like Hemophilia A
- Increased BT, PTT, normal platelet count
Hemophilia A
• ETIOLOGY: X-linked recessive, but 30% from new mutations
PATHOGENESIS: Factor VIII deficiency
SYMPTOMS: massive bleeds after trauma or surgery
• Spontaneous hemorrhages following minimal trauma to joints or muscles
DIAGNOSIS: prolonged PTT
• Normal platelets, BT, PT
TREAMTMENT: recombinant Factor VIII infusions → risk of transmission of viral disease
Lymphopenia
- ETIOLOGY: too few white blood cells
- Advanced HIV
- DiGeorge’s Syndrome
- Drug-Induced: chemotherapy, steroid therapy
- Autoimmune disease
- Acute viral infections
Neutropenia
- PATHOGENESIS:
- Reduced production (bone marrow issue):
- Suppression of myeloid stem cells (aplastic anemia)
- Suppression of myeloid precursors (drug-induced)
- Megaloblastic anemias, myelodysplastic syndromes
- Marrow infiltration (granulomas, tumors, inflammation)
- Kostmann Syndrome (acquired neutropenia)
- Accelerated consumption (peripheral issue):
- Splenic sequestration (splenomegaly)
- Overwhelming infection. (increased consumption)
- TREATMENT: G-CSF, broad-spectrum antibiotics (for infections)
- SYMPTOMS:
- Agranulocytosis: severe neutropenia, prone to life-threatening infection
- Usually drug-induced (chemotherapy)
Neutrophilic Leukocytosis
(too many cells)
- Infections: pyogenic bacteria
- Inflammation: MI, burns, trauma, surgery, gout, RA
- Acute hemorrhage
- Malignancy
Eosinophilic Leukocytosis
- Allergic disorders (asthma, hay fever)
- Skin diseases (bullous pemphigus, dermatitis herpetiformis)
- Parasitic infestations
- Drug reactions
Basophilic Leukocytosis
• Almost always indicates chronic myeloid leukemia
Monocyte Leukocytosis
- Chronic infections (TB, Rickettsiosis, Endocarditis, Malaria, SLE)
- Inflammatory Bowel Disease
Lymphadenopathy
- CHILDREN: reactive lymphadenopathy is common → nodes are tender with history of infection or rash ( NO biopsy)
- IN ADULTS: reactive adenopathy is less likely; there is increased concern for malignancy
- Fine needle aspiration or tissue biopsy
Leukemia:
neoplasia involves predominantly bone marrow
Lymphoma:
neoplasia forms discrete tissue masses (lymph nodes or extranodal)
Lymphoid Neoplasms
- LYMPHOMAS:
- 60% of NHL and all HL → non-tender lymph node enlargement
- 40% of NHL → extranodal (site-related symptom)
- B-cell neoplasms show light chain restriction, detectable by flow cytometry or immunohistochemical stains ( expressing either Kappa or Lambda chains)
- Non-Hodgkin’s Lymphoma (B-cell lymphomas = 90%)
- Precursor B-Cell
- Mature (Peripheral) B-Cell
- Precursor T/NK Cell
- Mature T/NK cell
- Hodgkin’s Lymphoma
- LEUKEMIAS: • Symptoms and signs related to bone marrow replacement → cytopenias
- PLASMA CELL NEOPLASMS:
- Bone destruction → bone pain due to fractures
- blood = M components
- Urine = Bence Jone Proteins
Follicular Lymphoma
- ETIOLOGY: middle aged 40-60 → tumor of germinal centers
- PATHOGENESIS: t(14;18) → Bcl-2 overexpression (anti-apoptosis)
- MORPHOLOGY: nodular vs. mixed/diffuse, small cells vs. large cells
- Diffuse pattern + many large cells = more aggressive
SYMPTOMS: painless, generalized lymphadenopathy, obstructive jaundice due to favoritism of 2nd part of duodenum
DIAGNOSIS: CD19, CD20, CD10+
• Often Stage IV at diagnosis
OUTCOME: 40% progress to Diffuse Large B-Cell Lymphomas (DLBL)
• Not curable
Diffuse Large B-Cell Lymphoma (DLBL)
- can be primary “De Novo” or Secondary to transformation of a pervious low grade lymphoma
- ETIOLOGY: 60 years old
- MORPHOLOGY: diffuse, large cells. Grow in sheets w/ mixed cells
SYMPTOMS: fever, weight loss, night sweats
- 60% present in late adulthood in lymph nodes (single mass)
- 40% present as an extranodal mass (GI tract, skin)
DIAGNOSIS: often Stage I or II at diagnosis
OUTCOME: moderately aggressive, but potentially curable
• Chemotherapy
Chronic Lymphocytic Leukemia (CLL) Small Lymphocytic Lymphoma (SLL)
- ETIOLOGY: CLL is the most common adult leukemia (WBC>4000) (BM → blood)
- 5% may present or progress to Small Lymphocytic Lymphoma (WBC<4000) (Only in lymph)
- MORPHOLOGY: almost mature lymphocytes → smudge cells (fragile)
- Bone marrow: Interstitial nodules
- Lymph node: diffuse pattern of small round lymphocytes
- SYMPTOMS: • Early: incidental finding of lymphocytosis
- Later: symptoms related to cytopenias + BM replacement
- Autoimmune hemolytic anemia / thrombocytopenia
- Enlarged lymph nodes, hepatosplenomegaly
- Recurrent infections
- DIAGNOSIS: CD5, CD19, CD20, CD23, CD43+
- OUTCOME: Cause of death: pancytopenia → recurrent infections
- Richter’s Transformation → progression to DLBL
Marginal Zone Lymphoma (MALToma)
• ETIOLOGY: lymphoma of small, mature lymphocytes
PATHOGENESIS: common site is stomach, superimposed on Helicobacter gastritis - antibiotic treatment of Helicobacter gastritis has caused regression of some earlier MZL’s
• Other sites: salivary gland or thyroid gland → secondary to autoimmune inflammation •
Graves / Hashimotos
- Sjorgens Syndrome
- Remain localized for long periods before spreading
- TREATMENT: antibiotics, resection
Burkitt Lymphoma (BL)
- ETIOLOGY: aggressive B-cell neoplasm associated with EBV
- African (endemic): 100% EBV → mainly kids / young adults
- HIV-associated: 25% EBV
- Sporadic: 15% EBV → mainly kids / young adults
PATHOGENESIS: c-MYC translocation to Ig heavy chain loci
- t(8;14)- most common
- t(2;8)
- t(8;22)
MORPHOLOGY: Starry-sky pattern → high mitotic rate + high apoptosis = increased macrophages
SYMPTOMS: presents as extranodal mass
- Africa (Endemic): mandible, abdominal viscera (kidneys, ovaries, adrenals)
- Sporadic: ileocecal
DIAGNOSIS: CD10, CD19, CD20
• Monospot (+) → Test for EBV/Mono
Hairy Cell Leukemia
• ETIOLOGY: rare, males > females
MORPHOLOGY: cells with round/kidney shaped nuclei and pale blue cytoplasm with thread-like extensions
- Bone marrow: infiltration of small lymphocytes (fried-egg appearance), enmeshed in reticulin
- Spleen: red pulp infiltration → beefy-red appearance
- SYMPTOMS: pancytopenia and splenomegaly
- DIAGNOSIS: CD11c, CD20, CD25, CD103+
- Fibrosis means marrow cannot be aspirated → Dry-Tap
- Good biopsy is important (TRAP stain positive)
Multiple Myeloma
- ETIOLOGY: 50-60 years, M > F, African American
- Monoclonal gammopathy
- SYMPTOMS:
- Plasma cells secrete IL-6 → osteoclasts → bone destruction (lumbar spine > ribs > skull) → back pain
- Bacterial infections due to neutropenia and hypogammaglobulinemia
- Renal insufficiency due to hypercalcemia, Bence-Jones proteins, AL deposition
- Organomegaly (spleen, liver, LN, lung)
- Pancytopenia - due to Marrow replacement
- MORPHOLOGY:
- PB: RBC Rouleaux formation (stack of coins)
- X-ray: punched out lesions in bone
- DIAGNOSIS:
- M-protein in serum or urine
- Bence-Jones protein in urine
- TREATMENT: chemotherapy (60% remission), BM transplant (if young)
Hodgkin’s Lymphoma
- ETIOLOGY:
- Classical HL: CD15+, CD30+, CD45-
- Nodular Sclerosis (65%)
- Mixed Cellularity (25%)
- Lymphocyte-predominant
- Lymphocyte-depleted (5%)
- Variant (L&H) HL: CD15-, CD20+, CD30-, CD45+
- Lymphocyte predominant
- SYMPTOMS:
- Nodular Sclerosis: adolescents/ young adults, stage I or II at diagnosis
- Mixed Cellularity: diffuse nodal replacement, EBV+, advanced stage at presentation
- Lymphocyte Depleted: elderly or HIV+, EBV+, advanced stage at presentation
- Variant HL: <35 years old, <5% transform to Non-Hodgkin’s B-cell lymphoma •
Enlargement of one or more lymph notes, pain in involved nodes after drinking alcohol, itching
- MORPHOLOGY: Reed-Sternberg Cell = bi-nucleated (owl-eye appearance) • Nodular Sclerosis: large nodules surrounded by thick fibrous collagen bands, Lacunar RS Cells
- Mixed Cellularity: eosinophilia (IL-5 secreted by RS cell)
- Variant: large nodules with no collagen fibrosis, RS cells called ”popcorn cells”
- STAGING: (1) single LN, (2) 2+ LN, (3) LN’s on both sides of diaphragm, (4) disseminated to organs
- COMPLICATIONS: long-term survivors get secondary cancers → AML, lung cancer
Acute Lymphoblastic Leukemia (ALL)
- ETIOLOGY:
- B-Cell types (85%) → CD10, CD19, CD20 → childhood
- T-Cell types (15%) → CD2-8, but no CD10 → adolescent males
- Associated with Down Syndrome - Granules + Auer Rod
- SYMPTOMS: abrupt and severe onset
- Bone pain
- Generalized lymphadenopathy
- Hepatosplenomegaly
- Testicular enlargement (B-ALL)
- CNS: headaches, blurred vision, vomiting (B-ALL)
- Thymic enlargement (T-ALL)
- PROGNOSIS:
- Good: 2-10 years old, low WBC count, Pre B-Cell, t(12;21), hyperdiploidy
- Poor: <2 years or teen/adult, >100,000 WBC, t(9;22), all other abnormalities
- TREATMENT: chemotherapy, but requires prophylaxis for scrotum •
DIAGNOSIS: PAS staining, TdT+
Acute Myeloid Leukemia (AML)
- ETIOLOGY: adult, >60 years old → 20%< increase in blast cells
- t(15;17), t(8;21) → best prognosis, t(16;16)
- Deletion/monosomy of chromosome 5&7 → worst prognosis
- Acute Promyelocytic (M3) → MPO, interferes with retinoic acid (RAR) receptor
- Acute Monocytic (M5) → No MPO, infiltration of gums
- Acute Megakaryocytic (M7) → No MPO, common in Down Syndrome
- PATHOGENESIS: translocations disrupt transcription factors for normal differentiation
- Chimeric genes → abnormal fusion proteins → block differentiation
- Aberrant tyrosine kinases → increased cellular proliferation •
MORPHOLOGY: irregular WBCs, punched-out nuclei with auer rods/MPO granules
- SYMPTOMS:
- Anemia → fatigue
- Neutropenia → fever, sepsis
- Thrombocytopenia → spontaneous bleeds
- DIC – M3 t(15;17) - bone pain + organ enlargement
- DIAGNOSIS: circulating blast cells, WBC count elevated (blasts count as WBCs), bone marrow aspirate
- TREATMENT: t(15;17) AML → All-trans-retinoic-acid (ATRA) → neutrophil differentiation, prevents DIC
- Combination chemotherapy and bone marrow transplantation
- treat with Vit A
Myelodysplastic Syndromes (MDS)
- ETIOLOGY: clonal maturation defects in stem cells → ineffective hematopoiesis → cytopenia
- Idiopathic/Primary: >50 years old, gradual onset
- Therapy-induced: 2-8 years old, post-chemo/radiation
- MORPHOLOGY
- PB: macrocytic anemia, cytopenias
- BM: hypercellular, but disorganized, ineffective hematopoesis •
SYMPTOMS
- Transformation to AML (10-40%)
- Death due to cytopenias
- DIAGNOSIS: <20% blast cells
- Abnormal chromosome 5&7
Chronic Myeloid Leukemia
- ETIOLOGY: defect in pluripotent stem cell for myeloid and lymphoid lineages → uncontrolled proliferation with full differentiation (especially granulocytes)
- M>F, 25-60 years old
- PATHOGENESIS: t(9;22) translocation → Bcr-abl → aberrant TK
- SYMPTOMS: gradual onset of tiredness, weakness, loss of weight and appetite, itching after hot showers, splenomegaly
- Stable Phase: 3 years without treatment
- Accelerated phase: 2-5 years → increasing blasts, fibrosis
- Blast crisis: acute leukemia
- DIAGNOSIS:
- PB: left-shifted leukocytosis ( increase in neutrophils, eosinophils, and basophils)
- BM: 100% cellular, increase granulocytic precursors ( increased megakaryocytes)
- TREATMENT: Imatinib (Gleevec) → inhibits TK
- Interferon-alpha → slows down disease
- Hydroxyurea → gentle chemotherapy
- BM transplant (effective in younger patients)
Primary Myelofibrosis
- PATHOGENESIS: JAK2 point mutations
- Increased megakaryocytes → increased TGF-b/PDGF → BM fibrosis → pancytopenia
- MORPHOLOGY:
- PB: nucleated RBC precursors (tear-drop shaped)
- BM: fibrotic, hypocellular
- SYMPTOMS: fibrosis of bone marrow causes pancytopenia
- Massive extramedullary hematopoiesis → hepatosplenomegaly
- DIAGNOSIS: Dry-Tap aspiration → thus biopsy must be done
Chronic Myeloproliferative Neoplasms
- Chronic Myeloid Leukemia (CML)
- Polycythemia Vera (PV)
- Essential Thrombocytosis (ET)
- Primary Myelofibrosis (MF)
- Disorders of a pluripotent progenitor cell, capable of uncontrolled proliferation with full differentiation.
- Tumour cells circulate &; home to 2º hematopoietic organs (spleen, liver) → organomegaly.
- Pathogenesis - Arise from a multipotent progenitor cells, capable of uncontrolled proliferation with full differentiation. Common pathogenic feature = mutated, constitutively activated tyrosine kinases circumvent normal growth controls. Result is growth factor-independent proliferation and survival of marrow precursors.
