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Carissa Romano RPA-C
  Touro PA Program
Types: Inherited, Autosomal Dominant, Acquired ( liver/kidney dz, chemo,
  Antithrombin III: inactivates surplus thrombin with help of heparin
        deficiency 25-60% causes venous thrombosis
        Fam hx: DVT/ PE
        First episode in 20’s
        Dx: decreased levels, resistance to heparin
        Mgmt: anticoag prior sx, symptomatic IV heparin then oral
  Protein C: vitamin K dependent stimulates fibrinolysis
      Deficiency causes recurrent DVT/PE, may have family history
      Normal PT, PTT, bleeding time
         Complications: coumadin induced skin necrosis, purpura fulminans in newborns
      Mgmt: Heparin then oral
          Inherited Thrombophilia
 Factor V Leiden is the most common cause of the syndrome
  accounting for 40 to 50 percent of cases.
 The prothrombin gene mutation, deficiencies in protein S,
  protein C, and antithrombin account for most of the
  remaining cases, while rare causes include the
   Venous thromboembolism
   Neonatal purpura fulminans
   Warfarin-induced skin necrosis
Diagnoses: Protein C/S/factor v leiden assay
              Acquired Hypercoagulability
Four Types:
  1. Pregnancy: increased venous stasis, hyperviscosity, decreased
       protein C/ antithrombin III, decreased fibrinolysis
  2. Malignancy: tumor cells activate platelets. 15% DVT/PE have
       Ca. 5% diagnosed within a yr
  3. OCP: women over over & smokers
  4. Lupus anticoagulant: seen with and without systemic lupus
       increases risk spontaneous abortions
Dx: hx, PE, doppler, CXR, VQ scan, spiral CT
Tx: heparin then coumadin/ greenfield filter
   Antiphospholipid Antibody Syndrome
 A disorder in which the patient has autoantibodies to complex of
  phospholipids and protein. It is associated with an increased risk of
  recurrent spontaneous abortions and arterial and venous
Two categories:Lupus anticoagulant & anticardiolipin antibody
Lupus: autoantibody against phospholipid and protein. Interferes
  with/prolongs phospholipid-dependent clottin (aPTT)
Anticardiolipin: antibodies measured in serum with specificity toward a
  specific phospholipid, cardiolipin
Diseases: connective tissue disorders, drug use, malignancy, acute infxn
• Doesn’t mean all pts at risk for thrombosis
• In the setting of an acute thrombosis, consider long term anticoags
                           Iron Overload
 Iron (Fe) in excess of bodily needs is deposited in tissues as
   Iron deposition resulting in tissue damage (or total body iron content
    > 5 g) is termed hemochromatosis.
   Focal or generalized iron deposition without associated tissue
    damage is hemosiderosis.
   Iron overload may occur as a primary (genetic) disorder of iron
    metabolism or secondary to other disorders that involve excessive
    intake or release of iron.
   Excess iron accumulates in nearly all tissues, but most morbidity
    results from deposition occurs in the liver, thyroid, pituitary,
    hypothalamus, heart, pancreas, and joints.
   Liver involvement can lead to elevated aminotransferase (ALT and
    AST) levels, bridging fibrosis, or cirrhosis.
 Focal hemosiderosis can result from recurrent hemorrhage within an
 Iron liberated from extravasated RBCs is deposited within that organ
   Hemosiderin deposits may eventually develop.
 M/c affected organ is the lung, and the cause usually is
   Recurrent pulmonary hemorrhage, idiopathic (eg, Goodpasture's
   chronic pulmonary hypertension
     (eg, primary pulmonary hypertension, pulmonary fibrosis, severe mitral stenosis).

 Can causes iron deficiency anemia, because iron in the tissue cannot be
   Inborn error in iron metabolism
   Increased iron absorption from the diet
   Iron overload
   Eventual fibrosis and organ failure
     Cirrhosis
     Cardiomyopathy
     Diabetes
     Hypogonadism
          Hereditary Hemochromatosis
 Autosomal recessive disorder
 Hemochromatosis gene (HFE)
 Most common single gene disorder
 1/250 – 1/300 white persons is homozygous for the gene
 1/10 carrier for mutation
 60-93% with disorder homozygous for the mutation C282Y
  (a cysteine–to-tyrosine substitution)
 Also C282Y/H63D compound heterozygosity
 Clinical manifestations often occur after age 40 OR when stores are
  15-40g do not develop until organ damage, often irreversible, develops.
Symptoms include:
   Fatigue
   cirrhosis – 95% Hepatomegaly, abdominal pain, elevated LFTS
   Bronze skin pigmentation –melanin (bronze) gray (iron)
   Loss of libido
   Arthalgias
   Diabetes
   Cardiomyopathy-conduction disorder
Influenced by:
   Age
   Sex
   Dietary iron
   Alcohol
   Blood loss in menstruation and pregnancy
   Unknown factors
Alcohol abuse and Hepatitis C accelerate
 Classic description:
  cutaneous hyperpigmentation and diabetes in a patient with
Diagnosis is based on serum iron studies and gene assay.
Treatment = serial phlebotomy weekly
    500 ml of blood, Removes 250 mg iron
   weekly until iron depletion
       Hgb < 120
       Ferritin < 50
       Transferritin saturation < 50%
    2-3 years may be required to remove >20g
 Long term maintenance about once every 3 months
 Desferrioxamine (DFO)
   Chelation therapy can lead to clinical improvement; however, it is
    almost never necessary because of the ease and efficacy of phlebotomy
    compared with chelation therapy.
 Avoid iron supplements, red meat, Vitamin C
 Avoid alcohol and tobacco, handling of raw seafood
 Currently screen in patients who have:
   Chronic liver disease
   Signs and symptoms associated with the disease
   A family history of iron overload
              Myeloproliferative disorders
 Myeloproliferative disorders are characterized by abnormal
  proliferation of one or more hematopoietic cell lines or connective
  tissue elements.
 clonal proliferation of a pluripotent stem cell, causing varying
  degrees of abnormal proliferation of RBC, WBC, and platelet
  precursors in the bone marrow.
   Essential thrombocythemia- thrombocytosis
   Myelofibrosis – marrow fibrosis with extramedullary heamtopoiesis
   Polycythemia vera- erythrocytosis
   Chronic myelocytic leukemia- granulocytosis
                  Essential Thrombocythemia
 Characteristics: Increased platelet count, megakaryocytic
  hyperplasia, and a hemorrhagic or thrombotic tendency.
 occurs between ages 50 and 70 yr.
 Symptoms and signs: may include
     Weakness
     Headaches (nonspecific)
     Paresthesias of hands & feet
     Bleeding- mild: epistaxis, easy bruising, GI
     Splenomegaly 60%/ hepatomegaly
     Digital ischemia.
     Hemorrhage
       In pregnant patients, thrombosis may cause recurrent spontaneous abortions.
                   Essential Thrombocytosis
   CBC, peripheral smear, bone marrow examination, and cytogenetics, including
    Philadelphia chromosome or ABL-BCR assay, should be obtained.
   platelet count > 500,000/μL, can be > 1,000,000/uL
     Platelet counts often decrease spontaneously during pregnancy
   normal RBC mass or normal Hct in the presence of adequate iron stores
   Absence of myelofibrosis
   The absence of Philadelphia chromosome (or ABL-BCR rearrangement-CML)
    and any other disorder that could cause thrombocytosis.
   Peripheral smear: platelet aggregates, giant platelets, and megakaryocyte
    fragments. The bone marrow shows megakaryocytic hyperplasia, with an
    abundance of platelets being released. Absence of teardrop-shaped RBCs
   Diagnosis also requires exclusion of any clinically suspected disorders that can
    cause secondary thrombocytosis
              Causes of Thrombocytosis
 Chronic inflammatory disorders:  Tumors:
   RA                              Hodgkin lymphoma
   Inflammatory bowel disease      Non-Hodgkin lymphoma
   TB                            Myeloproliferative:
   Sarcoidosis                     Polycythemia vera
   Wegener's granulomatosis        Chronic myelocytic leukemia
 Acute infection                   Sideroblastic anemia
 Hemorrhage                        myelodysplasia (5q- syndrome)

 Iron deficiency                   Idiopathic myelodysplasia

 Hemolysis
 Surgery: Splenectomy
                    Essential Thrombocytosis
Treatment is controversial; life expectancy nl, 2% leukemia
  • Because the prognosis is often good, potentially toxic therapies that
    lower the platelet count should be used sparingly.
  • Aspirin 81 mg/day po for symptoms & pregnancy
  • Patients > 60 yr and those with multiple comorbidities or previous
    thrombosis require myelosuppressive drugs to lower platelet counts.
     • lower the platelet count usually consists of anagrelide, hydroxyurea, interferon-
       alpha interferon can be used in pregnant women
     • Due to the long half-life of platelets (7 days), hydroxyurea
       and anagrelide do not provide an immediate effect
• The aim of therapy is a platelet count < 450,000/μL
 For immediate reduction in the platelet count, plateletpheresis has
  been used (eg, in serious hemorrhage or thrombosis; before an
  emergency operation); this procedure, however, is rarely necessary.
           Secondary Thrombocythemia
 Platelet function is usually normal.
 Abnormalities of platelet aggregation occur in about 50% of patients.
 Thrombocytosis does not increase the risk of thrombotic or
  hemorrhagic complications unless patients have severe arterial disease
  or prolonged immobility.
 With secondary thrombocytosis, the platelet count is usually <
  1,000,000/μL, and the cause may be obvious from the history,
  physical examination, or radiologic or blood testing.
 Treatment of the underlying disorder usually returns the platelet
  count to normal.
 Myelofibrosis is a chronic, usually idiopathic disease characterized
  by bone marrow fibrosis, splenomegaly, pancytopenia with
  immature and teardrop-shaped RBCs, and leukoerythroblastic
  blood smear.
   Extramedullary hematopoiesis
 Usually primary neoplastic transformation fibroblasts-collagen
 Secondary to a number of hematologic, malignant, or infectious
 Peak incidence 50-70 y.o
 Complicates CML and occurs 30% pts with polycythemia

 Treatment is usually supportive
 Early asymptomatic.
 Splenomegaly / 50% hepatomegaly
 later stages
   general malaise, weight loss, fever, or splenic infarction, may occur.
   Lymphadenopathy may occur but is not typical.
   Rapidly progressive acute leukemia develops in about 10% of patients.
 Idiopathic myelofibrosis should be suspected in patients with
  splenomegaly, splenic infarction, anemia, or unexplained elevations
  in LDH.
 If the disease is suspected, CBC should be obtained and peripheral
  blood morphology and bone marrow should be examined, including
  cytogenetic testing
 CBC, peripheral blood morphology and bone marrow with cytogenetic
  testing; exclusion of other conditions that can cause secondary
 Anemia is usual and generally increases over time.
   RBCs are normochromic-normocytic with mild poikilocytosis,
    reticulocytosis, and polychromatophilia.
   Nucleated RBCs & tear dropped may be in peripheral blood.
 WBC counts are usually increased but are highly variable.
   Neutrophils are usually immature, and myeloblasts may be present, even in
     the absence of acute leukemia.
 Platelet counts initially may be high, normal, or decreased;
   however, thrombocytopenia tends to supervene as the disease progresses.
 Bone marrow aspiration is usually dry.
   Because demonstration of marrow fibrosis is required and fibrosis may not
     be uniformly distributed, biopsy should be repeated at a different site if the
     first biopsy is nondiagnostic
Treatment is supportive, only palliative
   median survival is 5 yr from onset, initial diagnosis may be delayed.
   Constitutional symptoms, anemia, or some cytogenetic abnormalities
    suggest a poor prognosis; with anemia and some cytogenetic
    abnormalities, median survival is as low as 2 yr.
   No treatment reverses or controls the underlying process.
    Instead, therapy is directed at symptoms and complications.
 Androgens, splenectomy, chemotherapy, and splenic
  radiation therapy have sometimes been used for palliation.
 For patients with low erythropoietin (EPO) levels relative to the
  degree of anemia, EPO 40,000 units sc once/wk may increase
  Hct sufficiently; otherwise, RBC transfusion may be necessary.
 For younger patients with advanced disease, allogeneic marrow
  transplantation should be considered.
     Common causes of death:
 MI or heart failure 30%
 Hemorrhage 25%
 Acute leukemia 20%
 Infection 10%
                       Polycythemia vera
 Polycythemia vera (PV) aka erythrocytosis is the most common of
    the myeloproliferative disorders.
   Occurs in about 5/1,000,000
   More often in males (about 1.4:1)
   Mean age at diagnosis is 60 yr-5% of patients are < 40 yr at onset
   Characteristics: Excessive proliferation of erythroid, myeloid,
    and megakaryoid elements within the bone marrow.
     Leads to increased RBC mass and elevated peripheral granulocyte
      and platelet counts.
 Primary PV has nl EPO levels, leads to increased blood volume
     RBC mass normal but decreased plasma
 May progress to AML
                 Polycythemia Vera: CM
 Hepatosplenomegaly - 33%-                 LUQ pain
      extramedullary hematopoiesis          GI discomfort
 Hemorrhage - GU, cerebral,                Chest pain
  uterine, retinal                          Claudication- peripheral cyanosis
 Thrombosis - arterial/venous -            Pruritis- especially after hot shower
  cardiac, cerebral, peripheral, deep       Plethoric - ruddy appearance
  or superficial, portal                      Skin with deep red appearance
 Hyperviscosity & Hypervolemia             macroglossia
   Headaches, dizzinesss, Hypertension,    Erythromelalgia
    dyspnea, sweats, weight loss
                                              pathognomonic microvascular
 Gout - raised uric acid production           complication of PV or essential
 Blurred vision, Conjunctival                 thrombocythemia
  injection - retinal venous                  Burning pain in feet or hands
  engorgment                                   accompanied by erythema, pallor,
                                               or cyanosis
           Reactive Polycythemia Vera
Erythropoietin increase (Compensatory)
   High altitudes m/c
   Cardiovascular disease (cyanosis)
   Pulmonary disease – hypoventilation, COPD
   Increased Hg affinity
   Cigarette smoking
   Methemoglobinemia
           Pathologic Polycythemia vera
Erythropoietin increase (Inappropriate):
   Renal disease, renal cell ca
   Fibroma - uterine
   Hepatocellular carcinoma
   Hemangiomas
   Elevated androgen
Erythropoietin increase (Relative)
   Stress (Gaisbock’s syndrome)- HTN, obese middle age male smoker
   Dehydration
     Plasma loss - burn, enteropathy
     Overweight male on diuretic
                        Diagnostic study
 Hg >17.5 g/dl males >15.5 g/dl females
 RBC above 6.0/5.5
 Hct above 55%/47%
 Bone marrow:
   hyperplastic with panmyelosis, increased megakaryocytes
   RBC hypochromic, microcytic cells with reduced MCV, low Fe, absent
    Fe stores
                      Polycythemia vera
Criteria for diagnoses:
Erythrocytosis (RBC mass), absence of secondary polycythemia, and
  characteristic bone marrow changes (panmyelosis, enlarged
  megakaryocytes with clumping)
 Plus Any of the following:
   Splenomegaly
   Plasma erythropoietin level < 4 mUnits/mL
   Platelet count > 400,000 μLThrombocytosis - 50%
   Positive endogenous colonies
   In the absence of infection, neutrophil count >
    10,000/μLNeutrophilia - 50%
   A clonal cytogenetic abnormality in the marrow- hyperplastic with
                            Additional tests
 (total) increased - Hg/Hct/RBC elevatedIncreased blood viscosity
     RBC above 6.0/5.5
     Hct above 55%/47%
 Elevated serum B-12 & B-12 binding capacity due to elevated
   Urate increasedHg >17.5 g/dl males >15.5 g/dl females
   Elevated alkaline phosphatatase
   Increased expression of PRV-1 gene in leukocytes and decreased
    expression of C-Mpl (the receptor for thrombopoietin) in
    megakaryocytes and platelets
   Bone marrow:
     increased megakaryocytes
     RBC hypochromic, microcytic cells with reduced MCV, low Fe, absent Fe stores
 R/o secondary renal u/s IVP, CT abdomen, HgB electrophoresis
                          Polycethmia vera
 Treatment: Controversial PVSG
 Phlebotomy treatment yielded the best overall survival, but at the
  cost of increased thrombotic events during the first three years
 Myelosuppressive therapy reduced the incidence of thrombosis, but
  increased the risk of AML, lymphoma, gastrointestinal, and skin
   Initial: Phlebotomy- reduce Hct to 45%Reduce hypervolemia and
      decreases the risk of thrombosis, ameliorates symptoms; may be the only treatment
      Treatment of choice for women of childbearing age and patients < 40 yr because it
       is not mutagenic.
      Common thresholds for phlebotomy are Hct > 45% in men and > 42% in women.
      Initially, 300 to 500 mL of blood should be removed every other day
   Goal to Maintain a normal blood count
                   Other treatment options
 Venesection- in younger patients & mild disease. Results in Fe
  deficiency. Does not control platelet count.
 Hydroxyurea- Supplement phlebotomy with hydroxyurea (starting dose
  15 to 20 mg/kg per day) in patients who are at high-risk for thrombosis
  (age over 70, prior thrombosis, platelet count >1,500,000/microL,
  presence of cardiovascular risk factors).
 Anagrelide-reduces platelet function & number ; S/E CHF
 Phosphorus-32 - refractive pts; decrease thrombosis
   Associated with an increased incidence of acute leukemic transformation, and the
    leukemia that develops after this therapy is often resistant to induction
                    Polycythemia vera
 Death usually due to thrombosis and hemorrhage
 Thrombosis due to hyperviscosity, increased platelets and vascular
 Hemorrhage due to vascular distension, infarcts and defective
  platelet function
 Median survival – 6-18 months without treatment—withup to
  16 yrs
   Chronic Myelogenous Leukemia
General: a chronic myeloproliferative disorder characterized
  by excessive growth and development of differentiated cells
Incidence: increases with age
 Etiology: None identified; Age 40-60 years old
 Male:female 1.4:1
            CML- clinical manifestations
 marked splenomegaly with discomfort-/
 hepatomegaly
 Increased abdominal girth
 lymphadenopathy
 Fatigue, malaiseWeight loss, night sweats, anorexia
 Splenic enlargement with discomfort, pain
 Pallor, dyspnea, tachycardia (anemia)
 Easy Bruising, epistaxis, menorrhagia
 priapism
 Labs:
   Elevated WBC with presence of complete cell line(50,000-
   All myeloid cells on peripheral smear from blasts to mature
    neutrophils; basophilia possible
   Philadelphia chromosome 95% cases-translocation between
    chromosome 9 and 22, results in fusion protein (bcr-abl)
   Increased uric acidgouty arthritis after tx
   Low leukocyte alkaline phosphastase
     Distinguishes from leukemoid reaction
 Based on age and phase of disease
   Three phases: acute, chronic, blast phase
 Hydroxyurea as debulking agent to decrease WBC
 Nontransplantation-
   Interferon alpha
   Imatinib mesylate
 Transplantation therapy:
   Allogenic stem cell
                Chronic phase treatment
   Reduce total granulocytic mass with chemo- Chemo does not delay the
    acute transformation
   Length of phase: 3-5 yrs; can perform usual activities with oral chemo
 Treatment-
   Busuplhan & Hydroxyurea
   Allopurinol
   ?Splenectomy or irradiation
   Allogenic BMT under 55 years old - 50-70% cure
     if HLA-matching sibling excellent response to chemo in chronic phase-

 Median survival - 3-4 years, 20% > 10 yrs
Death usually from:
   Terminal acute transformation
   Intercurrent hemorrhage
   Infection
               Accelerated (Acute) Phase -
Occurs rapidly or over weeks- elevated leukocyte difficult to control with
 oral chemo, persistent thrombocytosis, increase in blasts, increased symp
Manifestations: Anemia, thrombocytopenia, Enlarged spleen, Bone
 marrow becomes fibrotic
   May last several months
TX: Difficult to control disease with chemotherapy
   May transform to lymphoblastic leukemia with temporary response to new
 New therapy may restore the chronic phase
 If transformation occurs - usually AML
 AML transformation = <12 month survival
                     Blast Phase
 Over several months, accelerated will transform to blast
   >30% blasts in peripheral blood or bone marrow
   Phenotype of blasts: usually myeloid but occasionally
    lymphoid, treatment for each phenotype is different
   Tx:with chemo some patients can be converted back into
    chronic phase
   Remission: short partial or complete
 CML Variants -
   Ph- CML- 9 to 22 oncogene may(not) be moved
   Juvenile CML Ph- Responds poorly to Rx
   Chronic Neutrophilic Leukemia
   Eosinophilic Leukemia
 3% Childhood & 25% adult ALL is Ph+
   course is ALL of poor prognosis
                          The end
 Review for test: including but not limited to
 Concentrate :
   on anemia, vit k def, b12, folate, ITP/TTP-HUS/DIC,
    anticoagulation, sickle cell anemia, hemolytic anemia,
    transfusion reaction, aplastic anemia, thalassemia, hemophilia,
    coag factor disorders, HSP, G6PD, spherocytosis
                      The white blood cell
Leukocytes: neutrophils ( granulocytes), monocytes, lymphocytes,
   eosinophil, basophil
Lifespan: 6-12 hours
 Chief defense against infection,
 WBC migrate to tissue, leave capillaries by passing through endothelial
   cells and penetrate connective tissue - diapedesis
 Granulocytes-(polymorphonuclear leukocytes)
 Specific granules; Nuclei with 2 or more lobes include:
      Neutrophils, eosinophils, basophils
      Lifespan few days-die by apoptosis (programmed cell death) in connective tissue
 Agranulocytes (mononucleaur leukocytes) no granules; lysosomes ;
  Nucleus round/ indented
      Lymphocytes and monocytes
                       White blood cell

 White cells = leukocytes
Two groups - phagocytes and immunocytes
1. Phagocytes =
  A. granulocytes ( neutrophils, eosinophils, basophils)
  B. monocytes
2. Immunocytes = lymphocytes and plasma cells
                 Myeloid Cell Line
Granulocyte-Macrophage Stem Cells (4,000 - 6,000/µl
    Granulocytic Stem Cells
       Neutrophils 50 - 70% of WBCs
         Segments = mature cells
         Bands = immature cells
       Eosinophils: 1 - 4%
         Increase during parasitic infections
       Basophils: < 1 %
         Involved in allergic reactions
    Monocytic Stem Cells
       Monocytes/macrophages
       2-8% monocytes of WBCs in blood
 Complete absence of granuloctyes
 Cause: drugs
 Complications: increased risk for infection and sepsis
 Bone marrow: no myeloid activity
 Treatment: immediate discontinuation of drugs, abx, and
  occasionally granulocyte transfusions if there is evidence of
 2-4% of leukocytes in normal blood
 Bilobed nucleus
 Characteristic: Many large elongated refractile specific
  granules stained by eosin
 Function: kills parasites such as schistosomes
 Eosinophilia: increase associated with allergic rxns and
  helminthic (parasites)
 Normal peripheral blood eosinophil count is < 350/μL,
 Diurnal levels that vary inversely with plasma cortisol levels; the
  peak occurs at night and the trough in the morning.
 The circulating half-life of eosinophils is 6 to 12 h
 Most eosinophils residing in tissues
 (eg, the upper respiratory and GI tracts, skin, uterus).

Factors that decrease the eosinophil count include:
   β-blockers, corticosteroids, stress, and (sometimes) bacterial and
    viral infections
 Eosinophilia is defined as a peripheral blood eosinophil count > 450/μL
Causes are myriad but often represent an allergic reaction or parasitic
  infection: NAACP
     Neoplasm
     Addison’s
     Allergic/Asthma
     Collagen Vascular
     Parasites
Hypereosinophilic syndrome- persistent eosinophilia in absence of
  cause with organ involvement: heart, liver, skin, lung, CNS
  Tx: steroids
Diagnosis involves selective testing directed at clinically suspected
  underlying causes.
Treatment is directed at the underlying cause.
Polymorphonuclear leukocytes
   60-70% circulating leukocytes
   Normal: Nucleus consists of 2.5-3 lobes linked by fine threads of
   Immature: neutrophils (band form) nonsegmented nucleus in shape
    of horseshoe
   Old: Neutrophils with more than 5 lobes are hypersegmented
   Two granules:
     specific (more abundant)
     azurophilic
   Action: Bacteria adheres to neutrophil, engulfed by pseudopod,
    bacteria is engulfed and granules work by digesting organism
   Pus: dead neutrophil, bacteria, semidigested material/ tissue fluid
 Neutropenia <2 x10^9
    Below .5x10^9 increased risk for serious bacterial infection
 Sites of infection: lungs, skin, urinary tract, oropharynx
 Causes:
      Drugs- chemo, phenytoin, procainamide, B-lactams, phenothiazines
      Bone marrow disorders- tumor infiltration & fibrosis
      Megaloblastic disorders
      Congenital-Kostmann’s syndrome
        Autosomal recessive
        Sepsis
    Autoimmune
    Collagen Vascular disease
    Hypersplenism-
        Felty’s Syndrome neutropenia from hypersplenism and anti-neutrophil antibodies
         in a patient with rheumatoid arthritis
 Treatment:
   Drug induced - remove Recovery -2 weeks
 Chronic neutropenia -
   mainly bacterial infections - antibiotics
   be aware of fungal & viral (herpes)
       Chronic Granulomatous Disease
 A rare disorder in which granulocytes and monocytes are unable to
  make superoxide anion and are thereby unable to kill phagocytosed
S/S: recurrent lymphadenitis, hepatic abscess, or osteomyelitis with
  family history of frequent infections
Diagnoses: Nitroblue tetrazolium test superoxide from normal
  phagocytes converts yellow dye to blue; antenatal diagnosis of X-
  linked CGD on cultured amniotic fluid cells
        Chediak-higashi syndrome
A rare autosommal recessive disorder with neutrophil
  dysfunction and large cytoplasmic granules in the
  granulocytes, monocytes and lymphocytes.

Clinical Manifestations:
 infants with increased susceptibility to infxn with
  neutropenia and a platelet function defect
 by flow cytometric demonstration of altered CD11b
  expression on the neutrophil cell surface
  1. Inflammatory process: infection, malignancy, burns,
        ischemic necrosis, post op states, gout, collagen vascular
        diseases, hypersensitivity reaction.
  2. Intoxications: uremia & DKA
  3. malignancy: CML, AML, and myeloproliferative disorders
  4. Misc: hemorrhage, eclampsia, hemolysis, exercise, post-ictal
  state, corticosteroids
  5. Chronic neutrophilia:
      complicate chronic therapy with steroids or lithium
      manifestation of certain endo disorders such i.e adrerocorticotropic hormone (ACTH)-
       or glutocorticoid-producing tumors or occasionally thyroid storm.
Toxic granulations: increase intensity in staining and # granules
  within neutrophils in pts with active infection
 Leukoctosis > 11X10^9
 Granulocytes predominate in most inflammatory states and counts as high as
  20,000/μl are not uncommon
   rarely may be as high as 40,000 to 50,000/μl.
 A leukemoid response: increase in WBC count to >25 x10^9 secondary to
  another condition.
   There may be a number of less mature forms present.
   A leukocyte alkaline phosphatase (LAP), which usually increases w/ increasing WBC,
    helps differentiate a leukemoid response from some myeloproliferative diseases such as
    chronic myelocytic leukemia
   differentiate from CML which has enlarged spleen, low leukocyte alkaline phosphatase
    with basophilia and philadelphia chromosome
Diagnoses: CBC with differential
Causes: infection & cancer
 Lymphopoietic organs
 Fetus - yolk sac, liver, spleen
 Post natal - BM & thymus
   Secondary tissues:
     lymph nodes, spleen, alimentary tract

 B cells, mature in bone marrow, and T cells, mature in the thymus.
 2 cell types are morphologically indistinguishable but have different
  immune functions
 Normal range 15% to 40%: Total lymphocyte count = 800–2600/mm3
   Total T lymphocyte = 800–2200/mm3
   CD4 lymphocytes = ≥400/mm3
   CD8 lymphocytes = 200–800/mm3
   Normal CD4/CD8 ratio is 2.0
                             B- lymphocytes

 B-Lymphocytes
   derived from BM stem cells
   B cells: About 5 to 15% of lymphocytes in the blood are B cells
     Present in the spleen, lymph nodes, and tonsils.
   Primary function is to manufacture and secrete antibodies
     They are identifiable by membrane expression of Ig (mIg) and by B cell–specific
      CD surface molecules;
     mIg can bind Ag, but subsequent B-cell activation depends on signaling through 2
      invariable molecules (Igα and Igβ).
     Express class II MHC molecules and various other non-B cell–specific CD
                         Immune Response
 Primary Immune response- a latent period of days before Ab is
   Initially, only IgM is produced.
   With the help of T cells, B cells can further rearrange their Ig genes
    and switch to production of IgG, IgA, or IgE.
   On first exposure, the response is slow and provides limited protective
 Secondary (anamnestic or booster) immune response- occurs when
  memory B and TH cells are reexposed to the Ag.
   Memory B-cells rapidly proliferate, differentiate into mature plasma
    cells, and promptly produce and release large amounts of Ab
     (chiefly IgG because of a T cell–induced isotype switch) into the blood and other
      tissues where Ab can react with Ag.
   After reexposure, the immune response is faster and more effective
Lymphocyte     Usual Cytologic              Laboratory Features         Clinical Features
Type           Disease Features
Small          CLL     B-cell surface       Hypogammaglobulinemia       Elderly; asympt
lymphocyte             markers with low     in 50%;(+) direct Coombs'   lymphocytosis only to
                       concentration of     test i15%; Node biopsy,     bulky disease with
                       surface              diffuse, well-diff.         adenopathy, splenomegaly,
                       immunoglobulin,      lymphocytic infiltrate      and ―packed‖ bone marrow
                       CD5 antigen

Atypical       Mono & Suppressor T-cell     Heterophil agglutinin; (+) Pharyngitis, fever,
lymphocytes    viral  markers               serology for               adenopathy, rash,
                                            EBV,CMV,toxo,HBsAg         splenomegaly, palatal
                                                                       petechiae, jaundice
Plasmacytoid   Waldenst Cytoplasmic IgM, IgM paraprotein, rouleaux,     Adenopathy, splenomegaly,
lymphocyte     röm's    periodic acid–Schiff cryoglobulins              absence of bone lesions,
               macroglo (PAS) positivity                                hyperviscosity syndrome,
               bulinemi                                                 cryopathic phenomena

Lymphobast     (ALL)    Terminal transferase Anemia, granulocytopenia, Peak incidence in
                        positivity, common thrombocytopenia,           childhood, acute onset,
                        ALL antigen, B- or T- hyperuricemia, diffuse   bone pain frequent
                        precursor markers bone marrow infiltration
Lympho Usual Disease        Cytologic Features          Laboratory Features            Clinical Features
Lymphosa Lymphocytic        B-cell surface markers with Nodular or diffuse, poorly     Middle-aged to older
rcoma    lymphoma           high concentration of       differentiated lymphocytic     adults, generalized
cell                        monoclonal surface          lymphoma on node biopsy,       adenopathy,
                            immunoglobulin              patchy, peritra-becular bone   constitutional
                                                        marrow involvement             symptoms
Sezary     CutaneousT- cell T-lymphocyte surface        Skin biopsy is diagnostic      Exfoliative
           lymphomas,       markers                                                    erythroderma,
           mycosis                                                                     cutaneous plaques or
           fungoides                                                                   tumors
Hairy cell Hairy cell       B-lymphocyte markers,       Pancytopenia                   Middle-aged males,
           leukemia         cytoplasmic projections,                                   moderate to marked
                            tartrate-resistant acid                                    splenomegaly
                            phosphatase, interleukin-2                                 without adenopathy
                            receptors, CD11 antigen
                                                                                       Elderly adults,
                        B-cell surface markers with                                    splenomegaly,
                        high concentration of                                          minimum
Prolymph Prolymphocytic surface immunoglobulin, Marked lymphocytosis                   adenopathy, poor
ocyte    leukemia       CD5 negative                (frequently >100 × 109/L)          response to therapy
                          T lymphocytes
 T - lymphocytes                      Ag attaches to APC complexed
   derived from BM stem cells          with HLA
   processed in the thymus            T cell must recognize Ag and self
   earliest T-cell is surface CD7+     HLA
   mature helper cells - CD4+           CD4 recognizes Class II (DP, DQ,
   suppressor cells - CD8+               DR)
                                         CD8 recognizes Class I (A,B,C)
 express 2 T-cell antigen
  receptors                            TCR joined with CD3 & signal T
   alpha-beta or gamma-delta           cell prolif.
 T cell receptor (TCR) :              IL1, 2 - released from ―activated‖
   Ag recognition portion has           T-cells, B-cells & APCs complexed
    alpha/beta or gamma/delta            induce proliferation &
    chains                                differentiation of clone
                     Clonal & maturation
 T & B cells have specific Ag receptors that bind to restricted number
  of Ags
   Result is T & B cell clones
 Colonal selection - Ags induce those clones to which they will bind to
 B cell receptor is identical to the immunoglobulin it secretes
   B cells mature to plasma cells
   Plasma cells secrete specific immunoglobul.
 Macrophages APC process Ag
   then present them to T & B cells
 T cells cannot bind Ag freely - require APC
  Produced by B cells & plasma cells
   IgG, IgA, IgM, IgD, IgE
   IgG = 80%
   IgA - two subclasses
   IgM - produced first, then IgG
   IgA - in secretions - gut
 Immunoglobulins
   IgD & IgE - delayed hypersen. reactions
   Two heavy & two light chains:
   gamma, mu, alpha, delta, epsilon
   kappa or lambda
 Plasma proteins enzyme system
 Lysis of bacteria or blood cells
 opsonize (coat) bacteria/blood cells for phagocytosis
 Nine major components forming a cascade
                Natural killer cells
 kill cells recognized as foreign
 directly recognize target structure on cell
 indirectly recognize structure via Ag-Ab complex attaching
  to Ab
 Lymphocytes> 5x10^9/L
 Causes: Viral infection
   (Epstein-Barr virus, cytomegalovirus, and hepatitis)
 Marked lymphocytosis: infectious mono, pertussis, chronic
  lymphoctic leukemia, and acute lymphocytic leukemia
                        Monocyte disorders
 Monocytosis
   m/c underlying malignant disease such as myelodysplastic or
    myeloproliferative disorders
   occasionally is a marker of underlying lymphoma or carcinoma
   chronic inflammatory/immune disorders
     mononucleosis syndromes
     collagen vascular disease
     inflammatory bowel disease
     sarcoidosis
     chronic infectious states (tuberculosis, SBE, syphilis)

 Monocytopenia
   nonspecifically result from marrow aplasia, HIV, hairy-cell leukemia,
    or treatment with radiotherapy, steroids, or interferon
              Infectious Mononucleosis
 Benign infection caused by Epstein-Barr virus, a herpes virus.
 B lymphicytes are infected.
 Atypical Lymphocyte = activated cytotoxic and suppressor T cells
  reacting against B cells infected with EBV
   Paracortical (T cell zone) in lymph node show expansion
 15-40 years old
 Prodrome - Lethargy
   Malaise
   Headaches/stiff neck
   Dry Cough
               Clinical manifestations
 Bilateral cervical tender lymphadenopathy
 Sore throat with inflamed pharynx/tonsils
 Fever - mild to severe
 Morbiliform rash, photophobia, headache
 Splenomegaly - 50%
 Hepatomegaly - 15%
 Jaundice - 5%
 Atypical Lymphocytosis: hallmark, not pathognomonic - peak day 7-10
 Heterophile antibodies Monospot test- peak week 2-3
   if high suspicion-repeat, (-)8wks, not IM, persist for 6 weeks, up to 1 yr
   Positive with HIV
 EBV capsid Ag antibody detected at 2-3wks
 EBV nuclear Ag antibody persists for life
 Mild Thrombocytopenia is frequent
 Often RPR positive/RF positive/ANA pos.
 A falling hematocrit may signal splenic rupture.
 An elevated left hemidiaphragm may occur in cases of splenic rupture.
   ALL, CMV, influenza, rubella, hepatitis, tonsillitis, HIV
   Symptomatic - Supportive rest-outcome not clear
   Splenectomy if rupture occurs.
   Transfusions for severe anemia or thrombocytopenia
   Pharmacologic therapy is not indicated in uncomplicated illness.
     Steroids in pts with severe thrombocytopenia or hemolytic anemia, airway obstruction
      2nd to enlarged tonsils.
       Prednisone, 60-80 mg PO qd for 3 days, then tapered over 1 to 2 wk.
       No role for antiviral agents such as acyclovir in the management of IM

 Eventual resolution of all symptoms is the rule.
 REFERRAL only in more than mild illness
INCIDENCE (IN U.S.): 27.1 cases/100,000 persons
   Varies widely by location       • 85% of cases in large cities
PREVALENCE (IN U.S.): 62 cases/100,000 persons
Sex: Males 84%, females 16% (through 1998).
   40% of newly reported U.S. cases in 1999 were in females.
Age: 80% between ages 20 and 40 yr
Familial disposition:
   no proven genetic predisposition
   individuals with deletions in the CCR5 gene are immune from infection with
    macrophage tropic virus (the predominant virus in sexual transmission).
   Congenital infection:
       1. Transmittable from an infected mother to the fetus in utero in as many as 30% of pregnancies.
       2. No specific congenital malformations associated with infection; low birth weight and spontaneous abortion
       are possible.
        • Neonatal infection: transmission possible to the neonate intrapartum or postpartum through breast-
1. In the United States, the cumulative number of persons who are HIV-infected is
   approximately 1 million.
2. Since the introduction of new antiviral therapy in 1996, AIDS-related morbidity and
   mortality rates have declined by 80%.
3. The overall percentage of persons with AIDS who are homosexual men has fallen (from
   80% in 1982 to 45% in 2005).
4. The percentage of men or women with AIDS whose risk behavior is heterosexual activity
   remains 20%.
5. Worldwide, 45 million people are living with HIV/AIDS.
6. Although only 10% of people with HIV/AIDS live in developed countries where
   antiretroviral agents are available, 90% of money for HIV care and prevention is spent in
   these countries.
7. Despite these disparities, major antiretroviral programs have been initiated in the
   developing world
             Acquired immunodeficiency
(AIDS) is a disorder caused by infection with the human
  immunodeficiency virus, type 1 (HIV-1) and marked by progressive
  deterioration of the cellular immune system, leading to secondary
  infections or malignancies

A retrovirus- RNA with 3 groups of structural genes
   1) group specific Ag (GAG)-encodes for proteins within the viral particle
   2) pol coding for reverse transcriptase - RNA to DNA in host cell
   3) env codes for envelope proteins
                 Transmission of HIV
 Virus transmitted via semen, blood, body fluids
 Transmitted during intimate sexual heterosexual or male
  homosexual contact inluding anal intercourse
 Infected mother to fetus or neonate as described previously
 Transmitted from blood & blood products
 IV drug users - blood transfusion dependent
   needle-sharing (during IV drug use,tattoos or transfusion)
 HIV infects T-helper cells (CD4)
 HIV lyses some CD4 cells (replication)
 HIV remains latent - unrecognized by the host immune system
   Progressive transformation of Bone marrow

 CD4 Ag - main receptor for HIV
 Cause of viral activation???
   cytokines??? other viruses???
 Following HIV infection intense viral replication results in high levels of
  HIV ribonucleic acid (RNA) and HIV p24 protein in plasma.
 Increases in anti-HIV antibody are detected.
 A variable window period (|---|) is present between the time of
  infection and the point at which evidence of infection is detected. HIV
  RNA levels are detected earliest, followed by HIV p24 antigen and
  finally HIV antibody production
         Initial infection CD4 cells >400/mm3
Acute infection occurs 2 to 6 weeks from the time of viral transmission.
    a. It most often is a mild, self-limiting mononucleosis-like illness;
         o pharyngitis, rash, splenomegaly, & lymphadenopathy (nontender, enlarged glands
           often persist for more than 3 months) Hepatitis and aseptic meningitis are
           occasionally seen.
    b. The p24 antigen and the HIV PCR will be reactive; positive HIV
       serology usually first becomes positive 1 month later.
         o Quantitative plasma HIV RNA at this stage predicts clinical outcome; those with high viral
           loads (>55,000 copies/m2) have a more rapid disease progression to AIDS than those with
           lower viral loads.
    c. CD4 cell counts subsequently decline an average of 75/mm3 per
       year, but the range is variable.
         o High levels of viral replication, 109 copies per day, occur at this stage even though
           the patient remains asymptomatic.
    d. Five percent of infected people are long-term nonprogressors;
       another 10% progress more rapidly.
2) Chronic symptomatic normal tests - may have low counts of all cells
3) Persistent generalized lymphadenopathy
   lab tests as in stage 2
4)Fully developed AIDS or AIDS-related conditions (CD4 cell count
  <200/mm3): the classic opportunistic infections
        a. (PCP), cerebral toxoplasmosis, cryptococcosis; CMV &
        Mycobacterium avium complex (MAC) occur at the most advanced stage, at CD4 c
        ell count below 50/mm3.
   fever, weight loss, diarrhea
   neurological disease - central or peripheral
   secondary cancers
     Kaposi’s sarcoma - vascular endothelial skin tumor
     NHL - squamous Ca of mouth/anus
          Opportunistic infection               Malignancies
 Disseminated strongyloidiasis         Kaposi's sarcoma in a person
 Disseminated toxoplasmosis               <60 yr of age
 Crypto/Histoplasmosis/salmonella        Primary brain lymphoma
 CMV/herpes simplex                      Invasive cervical carcinoma
 Atypical mycobacterial disease          High grade B cell non-
 Candiditis bronchopulm disease           Hodgkin's lymphoma
 Cryptosporidia spp. diarrhea            Burkitt's lymphoma
 Pneumocystis jiroveci pneumonia         Undifferentiated
 Extensive TB
                                           NonHodgkin's lymphoma
 Progressive multifocal
                                          Immunoblastic lymphoma
a.   Annual influenza vaccine each fall.
b.   Pneumococcal polysaccharide vaccine (Pneumovax) is recommended for all
         people with HIV infection and is most effective in those with CD4
         counts greater than 200.
c.    Invasive pneumococcal infections occur with increased frequency in HIV-
         infected people; these people should be revaccinated every 5 years.
d.    Haemophilus influenzae type b vaccine is not usually recommended for adult
         use, since the incidence of invasive H. influenzae infection is low.
e.   Hepatitis B vaccination is recommended for people who have no evidence of
         prior infection with hepatitis B and who are at risk for acquiring it.
f.   They should also receive hepatitis A vaccine.
g.   Tetanus-diphtheria vaccine boosters should be given every 10 years.
h.   Mumps and rubella vaccines are recommended for susceptible adults
              Differential Diagnoses
Other wasting illnesses mimicking the nonspecific features AIDS:
1. TB
2. Neoplasms
3. Disseminated fungal infection
4. Malabsorption syndromes
5. Depression
  • Other disorders associated with dementia or demyelination
  producing encephalopathy, myelopathy, or neuropathy
 absolute CD4 count 200 or <14% of total lymphocyte in the presence of
  proven HIV infection even in the absence of other infections- bad
 Detection of HIV antigen in blood
 Positive viral culture--CD4 cell count and HIV viral load measured every
  3 to 6 months
   Lag period - 3 month progressive pancytopenia & lymphopenia
   infections - autoimmune reactions - impaired marrow production
 Serological detection of Ab to HIV Ags - detection by enzyme-linked
  immunoabsorbent assay (ELIZA)
 Serological detection by western blot assay
 Reversed CD4:CD8 ratio (1.5-2.5:1)
       Three HIV viral antibody screening tests
a. Enzyme-linked immunosorbeut assay (ELISA)
         i. Bound anti-HIV antibody is detected by antihuman antibody labeled with
  an enzyme. The use of recombinant proteins has reduced false-positive results
  (specificity, 99.9%).
         ii. A false-negative finding may result when measured in the acute infection
  period (sensitivity, 99.9%).
b. Western blot confirmatory test is performed when ELISA is positive.
         a. Identifies specific viral antigens; it is (+) when both core and envelope antigens are present.
         b. Indeterminate when either antigen is present; if unchanged when repeated in 6 months in
           more than 1 laboratory this is called a false positive
c. New rapid serologic-screening assays
          i. HIV antigen–coated gelatin or latex particle agglutination assays. Single-use
   test can be performed rapidly, may be less sensitive and specific than standard
c. An oral salivary test called OraSure (sensitivity 99.9%) is sent to a reference
   laboratory after being inserted into the mouth for 2 minutes
 Aimed to prevent/treat infections
   prophylactic antibiotics/antifungals/pentamidine
 AZT - zidovudine - azidothymidine
 Acyclovir - for herpes
 Suramin - ribavarin - inhibit reverse transcriptase
 Vaccines - synthetic peptides corresponding to virus envelope
         False positive
 chronic alcohol use
 rheumatic disease
 congenital bleeding disorders
 syphilis
 neurocysticercosis.
 rheumatic diseases
 Sjögren’s syndrome
 Recent vaccination with hepatitis B or rabies vaccine
 influenza vaccination was reported to be associated with increased false-positive HIV
 multiparous women etiology remains uncertain.
 Recent infection with dengue, malaria, and hepatitis B
          Recommendations for HIV Testing
          Categories of Elevated Risk for HIV
 Homosexual men                   infection STD
 IVDU                             Hepatitis
 prostitution                     Confirmed or suspected tuberculosis
 Unprotected sex                  Geographic areas where HIV
 Illness or fever without          prevalence ≥1%
  cause                            Mandatory testing
 Patient request                    Federal prisons

 SpecificExposure                   Selected state prisons

   Occupational                     Pregnancy (Connecticut)

   High risk needle sharing or      Newborns (New York)
    sexual                           Court ordered
   Perinatal                        Immigration requirement
Lymphoproliferative disease

any clonal lymphoid disease, including
 lymphoma, myeloma, and leukemias
     Lymphoproliferative Disorders
 A clonal neoplastic proliferation of lymphocytes
 Types:
   CLL
   Hairy cell leukemia
   Hodgkins & Non-Hodgkins lymphoma
   Plasma cell dyscrasia
     Multiple myeloma & Waldenstrom macroglobulin
 Neoplastic proliferation of cells of the reticuloendothelial
 Lymphadenopathy is most common feature
 Involvement frequently involves marrow spleen liver, and
  extranodal sites

 Categories:
   Hodgkins
   Non Hodgkins
 Bimodal age distribution peak at 15-35 years old
     Smaller peak older than 50
 incidence of 3.2 per 100,000 population.
 Male:Female       2:1
   B-cell malignancy of unknown etiology
   EBV genome detected in 20-50% of cases
   ??Disease due to virus acquired later in life?
   Markers of definite lineage (T/B) not demonstrated except in
    lymphocyte predominant subtype (B cell)
                     Hodgkins lymphoma
 Usually present with painless,nontender,asymmetrical enlarged
  lymphadenopathy of supraclavicular nodes or cervical
   Left anterior cervical 60-70%, axillary 10-15%, inguinal 6-12%,
    mediastinal 6-11%
   30% present with systemic manifestations
 Spreads from one node to another invading local tissue
Diagnosis: Node biopsy- Reed Sternberg cells (single bi-lobed
  nucleus & large nucleolus with T cell inflammatory reaction)
     Effacement of nodal architecture
     Reed sternberg cells within polymorphic cellular background including small
      lymphocytes, histiocytes, plasma cells, and eosinophils
     RS cells express HLA class II antigens and IgG Fc receptors;RS cells express
      CD15 & CD25
                   Hodgkins lymphoma
 Splenomegaly - 50%
 Fever - 30% continuous or cyclic
   Pel-Ebstein fever
 Pruritis - 25%
 Night sweats
 Lymph node pain immediately after alcohol ingestion
 Weight loss - sweating(night) - fatigue
 Bone marrow involvement late in disease
                    Hodgkins lymphoma
 Eosinophilia is frequent
 Elevated ESR
 Progressive loss of immunologically competent T-cells
 Infections due to - herpes, CMV, fungal, TB
 With liver disease - increased transaminases
 With bone disease - hypercalcemia, hypophospatemia, increased alk.
 With biliary obstruction - increased bili.
                       Hodgkins lymphoma
 Histological Classification: based on the relative proportions of
  malignant cells, lymphocytes, and fibrosis

 With biliary obstruction - increased bili.
 With liver disease - increased transaminases
     1) Lymphocyte predominant - best prognosis
     2) Nodular sclerosis - cellular infiltrate may be of other three histological
         reticular or diffuse fibrosis pattern - worse prognosis
     3) Mixed cellularity
     4) Lymphocyte depleted -
                      Hodgkins lymphoma
 Colswlold Staging
   Stage I - one lymph node area involvement
   Stage II - two or more lymph node area involvement confined to one
    side of diaphragm
   Stage III - lymph nodes involved above and below the diaphragm
   Stage IV - extranodal involvement (marrow, liver,skin, GI)
 Staging:
   (A)Absence or (B)Presence of one or more of:
     fever, night sweats, weight loss (10%) - over 6 mos.
   Subscript E = localized extranodal extension - i.e. mediastinum into
    the lungs
   Lymph node & Splenic involvement = IIIs
                       Hodgkins lymphoma
 Clinical Staging -
   Chest x-ray - lung involvement
   Bone Marrow
   CT scan - thoracic, abdominal, pelvic
   MRI - in difficult cases
   Lymphangiograhy & Staging laparotomy - supplanted by CT & MRI
                        Hodgkins lymphoma
 Treatment:
   Stage I & IIA – radiation to involved & next adjacent nodes
   Stage I & II with bulky disease - add chemo.
   Stage IIB, III, IV – radiation & chemotherapy
   Stage IV – chemo alone
 Chemotherapy -
    1) Mustin, Oncovin, Procarbazine, Prednisolone (MOPP)
    2) Adriamycin, Bleomycin, Vinblastin, Dacarbazine (ABVD)
          ABVD - less likely to cause sterility or secondary leukemia
   Many alternate or hybridize both regimens
   Usually six cycles or four after full remission
   Relapses - new chemo regimen or autologous BM transplant - allows
    high dose chemo with/out radiation
              Hodgkins lymphoma
 Prognosis - five year survival:
   Stage I & II – 85-90%
   Stage IIIA - 70%
   Stage IIIB & IV – 50-70%
 Increased risk of rates of coronary artery disease, breast and
  lung cancer, myelofibrosis, leukemia (AML), and pulmonary
 Sterility - semen storage
                Non Hodgkins Lymphoma
 most common cancer ages 20 - 40 years old
 Incidence rate increases with increasing age, beginning after age 40.
 30,000 cases annually, 6th most common
 Etiologic factors have not been firmly established
   viral etiology between Burkitt’s lymphoma and Epstein-Barr virus has
    been supported.
   Lymphomas of the CNS are common in patients with human
    immunodeficiency virus (HIV) infection.
 No methods of prevention or early detection exist
 Disease is mostly that of B lymphocytes (85% of all NHLs)
   Nearly 90% of NHLs express B-cell surface antigens.
   Less than 10% - T-lymphocytes-clinically aggressive
   Some are neither B nor T - null cell
              Non Hodgkin’s Lymphoma
 Most arise from germinal follicle center cell
 Histology is either follicular (nodular/reticular) or diffuse
   Follicular pattern & disease with small lymphoid cells have favorable
   Disease with larger cells & blasts have poor prognosis
 Early hematogenous spread is a feature of NHL;
               Non Hodgkin’s Lymphoma
 Classification same as Hodgkins:
   Low grade malignancy (indolent) (5 yr survival 51%)
     small lymphocytic cell, follicular cell (small, mixed or large): well & poor
        well differentiated-older pt, generalized lymphadenopathy, HSM,
        PDLL-middle aged, lymphadenopathy with infiltration of bone marrow, liver &
     Small lymphocytic lymphomas related to CLL
     Patients with indolent lymphoma (such as follicular lymphoma) usually have
      disseminated disease at presentation
   If asymptomatic and size or location poses no threat - watch
      I, Ie, II - local radiotherapy
      In advanced disease or with systemic symptoms chemotherapy
         continuous or intermittent but cure is not achieved
           - autologous marrow transplant to cure patient
                         Staging: Intermediate
 Intermediate grade malignancy (aggressive) ( median 2 yr survival)
     follicular cell, diffuse cell (small, mixed, large) Diffuse large cell (DLCL)
          Patients with follicular cell lymphoma: middle age & benign course
          may transform to blast cell
   Treat with chemo and occasionally
     Localized disease - combination chemotherapy:
   CHOP Cyclophosphamide, Hydroxydaunorubicin (Adriamycin),
    Oncovin (vincristine), Prednisolone followed by irradiation to involved
   Stage I or II bulky disease or stage III or IV - intensive cyclic CHOP or
    M-BACOD (MTX, bleomycin, adriamycin, cyclophosphamide, vnc,
          remission rates of 75% & disease free survival long term - 30-50 %
                       High grade malignancy
 (highly aggressive fatal 3-6 months)
      Relatively uncommon
      70% cured with treatment
      large cell immunoblastic,
         Immunoblastic types: widespread nodal destruction with spread into surrounding
          tissue (GI tract, spinal cord, renal)
         compromised immunity; usually in children & derived from maignant T cell
      lymphoblastic cell- mostly children & younger adults, bimodal 2nd peak in 70’s
         Thymoma with T cell markers, uniform size, scant cytoplasm, delicate chromatin,
          & absent nucleoli; clinically & morphologically into ALL
      small non cleaved cell-kids-
      Burkitt-eastern africa-caused by EBV, arise in jaw & disseminates rapidly, nonBurkitt
   Treatment is combined Chemo with or without radiation
 Specific chromosomal abnormalities have been associated with these
  histologic subtype t(14:18), t(11:14)
  High grade malignancy Treatment
 Localized grade I - radiotherapy
 Otherwise chemotherapy and radiation
   MACHO - mtx, cytosine arab, cyclophos, adria, vnc
 Response is good but relapse is high
 CNS prophylaxis required in young subjects
 Allogeneic or autologous BMT after first remission should be
                 Non Hodgkin’s Lymphoma
Diseases predisposing to NHL
   Immune deficiencies inherited or acquired
      AIDS
      following transplantation
      following treatment of Hodgkin’s Lymphoma

Clinical Presentation
 Asymptomatic painless superficial lymphadenopathy
 A prior history of previous lymph node enlargement with regression
  ('waxing and waning') is common with indolent lymphomas
 A rapid, progressive enlargement is suggestive of a more aggressive
                  Clinical Presentation
 Asymptomatic painless superficial lymphadenopathy
   A prior history of previous lymph node enlargement with regression
    ('waxing and waning') is common with indolent lymphomas
   A rapid, progressive enlargement is suggestive of a more aggressive

 Systemic complaints: fever, night sweats or weight loss (40%) with
   these are 'B' symptoms and are important, as they are of prognostic
   Less common features include fatigue, malaise and pruritis
                   Clinical Presentation
 Fever, night sweats, weight loss      Oropharyngeal involvement (5-
 Hepatosplenomegaly abdominal           10% cases)
  distension, ascites, patches of         sore throat, noisy or obstructed
                                      Anemia, neutropenia (infections),
 GI symptoms: early satiety,
                                       thrombocytopenia (purpura)
  N/V/D/C due to intra-
  abdominal lymphadenopathy;          Dysuria, polyuria or nocturia due
   epigastric pain is common
                                       to pelvic lymphadenopathy
    presentation for GI MALT          Persistent itching
    lymphoma                          Enlarged
 Dyspnea, cough or chest pain         mesenteric/retroperitoneal
  due to intra-thoracic                nodes
               Ann Arbor staging classification
 Stage I: involvement of a single lymph node region (I), or localized involvement of a single
   extralymphatic organ or site (IE)

 Stage II: involvement of two or more lymph node regions on the same side of the diaphragm
   (II), or localized involvement of a single associated extralymphatic organ or site and its
   regional lymph node(s) with or without involvement of other lymph node regions on the
   same side of the diaphragm (IIE). The number of lymph node regions may be indicated by a
   subscript, e.g. II3

 Stage III: involvement of lymph node regions on the both sides of the diaphragm (III), which
   may also be accompanied by localized involvement of an associated extralymphatic site or
   organ (IIIE), by involvement of the spleen (IIIS), or both (IIIE-S)

 Stage IV: disseminated (multifocal) involvement of one or more extralymphatic organs with
   or without associated lymph node involvement, or isolated extralymphatic organ involvement
   with distant (nonregional) nodal involvement
                Non Hodgkin’s Lymphoma
 Staging is identical as for Hodgkin’s disease

 Each stage is subdivided into ―A‖ and ―B‖ categories based on the
  absence or presence, respectively, of systemic symptoms

 Prognosis is related to histology not stage

 For staging
   tissue specimen
   Chest x-ray
   CT or MRI abdomen/pelvis disease
   Bone marrow biopsy, aspirate
 5-10% patients have extranodal disease
 Prognosis related to histology BUT
   over 60-65 y.o. - poor prognosis
   multiple sites of extranodal disease
   elevated LDH
   bulky disease (>5cm mass)
   prior history of disease/AIDS
         Non hodgkins lymphoma
 Relapses
   Re-induction with chemo followed by intensive
    chemotherapy/radiotherapy followed by autologous BM
   Purge the marrow with monoclonal antibodies
 Prognosis
   Low-grade disease- good survival 5-10 years
   High grade disease- 40-50% survival 2 years
                    Burkitts lymphoma
 B-lymphoblastic lymphoma-Proliferation of BM plasma cells
 Peak incidence seventh decade
 Massive jaw lesions(Africa), extranodal abdominal (US) & ovarian
  involvement in African children
   Dense collections lymphoid cells with macrophages intermixed, the
    macrophages have a clear space around the, giving tissue a Starry
    Sky‖ appearance
 Lytic bone lesions
 EBV in cells t(8:14)
 Chemo- dramatic remissions, but relapses are frequent.
  Autologous BMT
 Monoclonal protein in serum and urine
                         Burkitts lymphoma
 Diagnosis:
   Monoclonal protein in serum and/or urine
   Paraprotein is IgG-66%, IgA-33%, rarely IgM, IgD
   Normal serum immunoglobulins are depressed
   Bence-Jones protein in urine - 33%
     free light chains - either kappa or lambda
   BM - increased plasma cells often with abnormal forms - ―myeloma cells‖
     Moderately large cells with round, multiple nuclei, lipid containing vacuoles,
      macrophages with ingested debris
   Plasma cells are monoclonal B cells
   Osteolytic skeletal areas - 80%
   Abnormal plasma cells in blood film - 15%
   Elevated ESR
   Elevated serum Ca
Burkitts lymphoma
 Diagnosis:
   Elevated serum alk. phos. with fractures
   BUN over 14 mmol/l
   Renal failure due to:
     Deposits of B-J protein in kidney
     hypercalcemia
     elevated uric acid
     deposits of amyloid
                    Plasma disorders
 Plasma cell disorders are a diverse group of disorders of unknown
  etiology characterized by the disproportionate proliferation of
  one clone of B cells
 presence of a structurally and electrophoretically homogeneous
  (monoclonal) immunoglobulin or polypeptide subunit in serum
  or urine.
 Plasma cell disorders are of unknown etiology
 Characterized by the disproportionate proliferation of one clone.
  The result is a corresponding increase in the serum level of its
  product, the monoclonal immunoglobulin protein (M-protein).
                           Heavy chain diseases
Neoplastic plasma cell disorders-overproduction of monoclonal immunoglobulin heavy chains.
  considered in pts with s/s of lymphoproliferative disorders; more lymphoma than MM
IgA heavy chain disease- m/c of all; ages 10 and 30 Middle East
    Immune response to a parasite or other microorganism.
    Villous atrophy and plasma cell infiltration of the jejunal mucosa is usually present
    The course is highly variable: Some patients die in 1 to 2 yr, whereas others have remissions that last
     many years, particularly after treatment with corticosteroids, cytotoxic drugs, and broad-spectrum
IgG heavy chain disease- primarily in elderly men but can occur in children.
    RA, Sjögren's syndrome, SLE, TB, myasthenia gravis, hypereosinophilic syndrome, autoimmune
     hemolytic anemia, and thyroiditis.
    Rdxn nl Ig levels occur, amyloidosis , lymphadenopathy, HSM, fever, and recurring infections.
     Pancytopenia with eosinophilia and circulating plasma cells
    aggressive disease survival is about 1 yr.
IgM-adults > 50 yr.
    Visceral organ involvement (spleen, liver, abdominal lymph nodes) is common;
     hypogammaglobulinemia/ Bence Jones
    BM: vacuolated plasma cells are pathognomonic.
    Death can occur in a few months or in many years.- tx like lymphoprolif disorder it resembles
 Routine blood tests, protein electrophoresis, x-rays, and bone marrow examination.
 Protein electrophoresis is performed on serum & urine sample concentrated from a
   24-h collection.
    M-protein in about 80 to 90% of patients. (M-spike)
       Immunofixation electrophoresis can identify the immunoglobulin class of the M-protein and can often
         detect light-chain protein if the serum immunoelectrophoresis is falsely negative
    Bence Jones protein) or IgD. 10 to 20% free monoclonal light chains
    Bence Jones proteinuria > 300 mg/24 h,
    Serum level of β2-microglobulin is frequently elevated and correlates with myeloma cell mass.
 X-rays: Punched-out lytic lesions or diffuse osteoporosis is present in 80% of cases.
 Bone marrow aspiration and biopsy are usually performed.
    Rouleaux: sheets or clusters of plasma cells diagnostic of marrow tumors; marrow involvement is
      patchy, and only increased numbers of plasma cells at various stages of maturation may be found.
      Still, the number of marrow plasma cells is rarely normal. Plasma cell morphology does not
      correlate with the class of immunoglobulin synthesized.
                          Multiple Myeloma
 Multiple myeloma, or plasma cell myeloma, is a disease caused by the
    proliferation of neoplastic plasma cells that synthesize abnormal amounts of
   The proliferation of plasma cells takes place in the bone marrow and causes
    associated destructive osteolytic lesions.
   These abnormal cells are a monoclonal population of B cells that secrete the
    same immunoglobulin subclass and the same light chain (κ or λ).
   Multiple myeloma accounts for 10% of hematologic malignancies and 1% of all
   Incidence of 3 to 4 per 100,000.
   More common in blacks, exposure to alkylating agents, asbestos, and pesticides
   The median age at diagnosis is 65 years
                          Clinical Manifestations
 Bone pain- especially at night back or chest, less often in extremities is present at time of
    diagnoses 2/3
   Pathologic fractures caused by tumor invasion, can have cord compression from
   Diffuse osteoporosis or discrete osteolytic lesions develop, usually in the pelvis, spine, ribs,
    and skull.
    Hypercalcemia, hyperuricemia
   Anemia & pancytopenia
   renal insufficiency (myeloma kidney)
      extensive cast formation in the renal tubules, atrophy of tubular epithelial cells, and
       interstitial fibrosis.
    recurrent infections -defective cellular immune function
   neuropathies caused by direct tumor compression
   hyperviscosity, bleeding, and thrombosis
   Secondary amyloidosis 10%
                           Multiple myeloma
Prognosis: Leukemia may be a late feature
   7 mo untreated
   3 to 4 yr with conventional therapy
   4 to 5 yr with high-dose therapy and stem cell transplantation.

Unfavorable prognostic signs at diagnosis:
   high levels of M-protein in serum or urine,
   elevated serum β2-microglobulin levels (> 6 μg/mL)
   diffuse bone lesions
   hypercalcemia, anemia, and renal failure
   If BUN > 14mmol/l at presentation - median survival few months.   If
    BUN < 7mmol/l at presentation - median survival 33mos.
                                Multiple myeloma
 Treatment to improve quality of life: Supportive measures:
    Hydration & ambulation
    Bisphosphonates, analgesics and palliative doses of radiation therapy (18 to
     24 Gy) can relieve bone pain.
       impare pts ability to receive cytotoxic doses of systemic chemotherapy.
    Anemia – PRBC, Recombinant erythropoietin (40,000 units sc q wk)
    Plasmapheresis- hyperviscosity symptoms
    Chemotherapy - oral melphalan & prednisone, avoid alkylating agents
    Allopurinol-renal insufficiency or hyperuricemia symproms
    Autologous peripheral blood stem cell transplantation is considered for patients < 70 yr who
     have adequate cardiac, hepatic, pulmonary, and renal function, particularly those whose
     disease is stable or responsive after several courses of conventional chemotherapy
    interferon, which prolongs remission but has adverse effects
 Pneumococcal and influenza vaccines
 Prophylactic abx not recommended; IVIG for recurring infxn
           Waldenstrom Macroglobulinemia
 Lymphocyte with plasma cell features. The disease is commonly
    referred to as a lymphoplasmacytic disorder (b/c morphology)
   S/S: weakness, fatigue, oral/nasal mucocutaneous bleeding,
    hyperviscosity (HA, blurred vision, deafness, weakness,
   PE: lymphadenopathy with hepatosplenomegaly; rarely have bone
   Paraproteins: involves monoclonal IgM paraprotein, whereas in MM
    IgG and IgA are most common involved
   Tx: same as low grade lymphoma & MM, ie oral alkylating agents
   Median survival: 3-5 yrs
 Oncogenes (Protooncogenes) = normal gene
   Code for proteins for cellular proliferation, survival, differentiation
   Changes in their function lead to malignant transformation of normal
   Changed by retroviruses in animals - tumors
   Oncogenes named after mammalian species with virus induced tumors
 Tumor suppressor genes = anti-oncogenes
 Their products inhibit cell division/prolifer
 Regulate cell passage from G1-S-G2-M
 Loss of one allele predisposes to tumor - this may be inherited
                  Hematologic Malignancies
 Activation of oncogene or loss of function of tumor suppressor
    gene can result in malignant transformation
   Multiple alterations in one oncogene
   Changes in two or more oncogenes or tumor suppressor genes
   Disease Monitoring
     Initial diagnosis
     For prognosis - Ph+ in ALL = poor prognosis
                   Hyperdiploidy ALL = favorable
     Monitoring response to therapy
         cytogenetic analysis (detect minimal residual disease
 Acute
   A fulminant disease that if untreated is fatal within weeks to months
   Immature leukocytes proliferate and accumulate in marrow with loss of
    normal marrow elements
     Types:
     Acute Myelocytic Leukemia
     Acute Lymphocytic Leukemia

 Chronic
   Proliferative disease of mature leukocytes
   May remain stable and asymptomatic for years
     Types:
       Chronic Myelocytic Leukemia
       Chronic Lymphocytic Leukemia
 Both acute and chronic leukemias are further classified
  according to the prominent cell line involved in the
     If the prominent cell line is of the myeloid series it is a myelocytic
      leukemia (sometimes also called granulocytic)
     If the prominent cell line is of the lymphoid series it is a lymphocytic
     Therefore, there are four basic types of leukemia
          o Acute myelocytic leukemia – AML- (includes myeloblastic,
            promyelocytic, monocytic, myelomonocytic, erythrocytic, and
          o Acute lymphocytic leukemia – ALL- (includes T cell, B cell,
            and Null cell)
          o Chronic myelocytic leukemia – CML - (includes myelocytic
            and myelomonocytic)
          o Chronic lymphocytic leukemia – CLL - (includes plasmocytic
            {multiple myeloma}, Hairy cell, prolymphocytic, large granular
            cell lymphocytic, Sezary’s syndrome, and circulating lymphoma)
       Predisposition to Malignancies
 Heredity-Down’s
 Fanconi anemia
 Ataxia telangiectasia
 Siblings- Twin ALL
 Radiation & Chemicals- benzene, alkylating agents
 Viruses: in Africa all with Burkitt’s have (+) EBV
                       Acute Leukemia
 Clonal proliferation from a single abnormal stem or progenitor cell
 Blast cells fail to differentiate but divide - result is bone marrow
  failure - replacement
 ALL - common form in children - peak 3-5y
   Common CD10+ precursor B type = equal sex distribution
   T-ALL - null (CD10-) -male predominance
 AML - occurs in all ages
   AML - common form of acute leukemia in adults
   AML - 10-15% of childhood leukemia
Acute leukemias can occur in all age groups:
     ALL is more common in children
     AML is more common in adults

Chronic leukemias are usually a disease of adults
     CLL is extremely rare in children and unusual before
            the age of 40
     CML has a peak age of 30-50
  Comparison of acute and chronic
                           Acute                    Chronic
Age                       all ages           usually adults
Clinical onset             sudden            Insidious
Course (untreated)        6 mo. or less      2-6 years
Leukemic cells       immature >30% blasts    more mature cells
Anemia                     prominent         mild
Thrombocytopenia          prominent          mild
WBC count                 variable           increased
Lymphadenopathy           mild              present;often prominent
Splenomegaly              mild              present;often prominent
Cell Line
              Peripheral Smear
Normal blood cell      Leukemia        Platelet
                                Red Cell          Blasts
                       White Cell

                              Blood with leukemia
                             Clinical Features:
 Bone Marrow Failure (replacement)
   Pallor - lethargy – dyspnea- fatigue-malaise,
   Fever - malaise - mucous/skin lesions
   Bruises - purpura - bleeding gums
   Hypermetabolic: weight loss-tachycardia-chest pain
 Organ infiltration
   Bone pain
   Lymphadenopathy - Hepatosplenomeg. (ALL)
   Gum hypertrophy
   Meningeal syndrome - headaches, nausea, vomiting, blurred vision, diploplia,
    papilloedema, irritability, cranial nerve palsies, seizures, and papilledema is uncommon
   Testicular swelling (ALL)
   leukemia cutis (a raised, nonpruritic skin rash).
 Laboratory findings:
   anemia, white count in(de)creased, normal
   thrombocytopenia - smear shows blasts
Morphology – an experienced morphologist can look at the size of
 the blast, the amount of cytoplasm, the nuclear chromatin pattern,
 the presence of nucleoli and the presence of auer rods (are a pink
 staining, splinter shaped inclusion due to a rod shaped alignment of
 primary granules found only in myeloproliferative processes) to
 identify the blast type:
          AML – the myeloblast is a large blast with a moderate amount of cytoplasm, fine lacey
           chromatin, and prominent nucleoli. 10-40% of myeloblasts contain auer rods.
          ALL – in contrast to the myeloblast, the lymphoblast is a small blast with scant
           cytoplasm, dense chromatin, indistinct nucleoli, and no auer rods
Cytochemistry – help to classify the lineage of a leukemic cell
  (myeloid versus lymphoid)
          Myeloperoxidase – is found in the primary granules of granulocytic cells
           starting at the late blast stage. Monocytes may be weakly positive.
                       Sudan Black
Sudan black stains phospholipids, neutral fats and sterols found in
primary and secondary granules of granulocytic cells and to a lesser
extent in monocytic lysosomes. Rare positives occur in lymphoid
                Nonspecific esterase
Nonspecific esterase – is used to identify monocytic cells which are
diffusely positive. T lymphocytes may have focal staining
               Acid phosphatase
 Acid phosphatase may be found in myeloblasts and
  lymphoblasts. T lymphocytes have a high level of acid
  phosphatase and this can be used to help make a diagnosis of
  acute T-lymphocytic leukemia
        Leukocyte alkaline phosphatase
 Leukocyte alkaline phosphatase – is located in the tertiary granules
  of segmented neutrophils, bands and metamyelocytes. The LAP
  score is determined by counting 100 mature neutrophils and bands.
  Each cell is graded from 0 to 5. The total LAP score is calculated
  by adding up the scores for each cell
Chromosomal Karyotyping
Myeloblast with Auer rods
         Acute lymphoblastic leukemia
 Primarily a disease of children 80% ALL
 Peak incidence at 4 years old
 Adult ALL more refractory to therapy than kids
   In adults peak age older than 65
 20% have T-lymphocyte surface markers
   Majority have neither T or B surface markers
 deoxyribonucleotidyl transferase detected in malignant cells
         Acute lymphoblastic leukemia –
 They may be classified on the basis of the cytological features of the
  lymphoblasts into;
   L1 - most common form, found in children, best prognosis.
      Cell size is small with fine or clumped homogenous nuclear chromatin and absent
       or indistinct nucleoli. The nuclear shape is regular, occasionally clefting or
       indented. The cytoplasm is scant, with slight to moderate basophilia and variable
   L2 – most frequent ALL found in adults.
     Cell size is large and heterogenous with variable nuclear chromatin and prominent
       nucleoli. The nucleus is irregular, clefting and indented. The cytoplasm is variable
       and often moderate to abundant, the basophilia is variable and may be deep, and
       vacuoles are variable.
   L3 – Rarest form of ALL; Burkitt’s leukemia/lymphoma
     Cell size is large, with fine, homogenous nuclear chromatin containing prominent
       nucleoli. The nucleus is regular oval to round. The cytoplasm is moderately
       abundant and is deeply basophilic and vacuolated. <5%
                  Clinical findings Acute
                 lymphoblastic leukemia
 Lymphadenopathy (50%) not AML    irritability,
 Hepatosplenomegaly (2/3 ALL)     anorexia,
   Hepatomegaly uncommon AML      infection,
 pancytopenia with resulting      bleeding,
                                   bone pain,
 pallor,
                                   without marked elevations
 fever,                            in WBC
 weight loss,
 Presence of circulating leukemic blast cells on peripheral smear,
  bone marrow aspirate, and biopsy.
 Histochemical stains, flow cytometry, and cytogenetics are useful
  in subtyping and determining treatment options
   Flow cytometry is gold standard
   Periodic acid-Schiff histochemical stain is positive in ALL
   Myeloperoxidase histochemical stain is positive in myeloid leukemias
 30% have WBC >50,000
 Marrow biopsy immature cells
                         ALL prognosis
           Favorable prognostic             Unfavorable factors
                                       Pseudodiploidy
 are age 3 to 7 yr
                                       Lymphadenopathy
 WBC count < 25,000/μL
                                       WBC > 50,000
 FAB L1 morphology
                                       HSM
 Hyperdiploidy
                                       Ph chromosome t(9;22)
 Pro-B-cell phenotype
                                       Non T cell phenotype
 Complete reduction chemo
                                       age >10
 leukemic cell karyotype with > 50
                                       African American
  chromosomes and t(12;21)
                                       L3 morphology
 no CNS disease at diagnosis
                                       hypoploidy
                                       B-cell phenotype.
                              Acute Leukemia
   Four general phases ALL include remission induction, CNS prophylaxis,
    postremission consolidation or intensification, and maintenance
   Remission can be induced with daily oral prednisone, weekly IV
    vincristine & anthracycline or L-asparaginase. Complete remission rate is
     Important site of leukemic infiltration is the meninges
         prophylaxis and treatment may include high-dose intrathecal methotrexate,
          cytosine arabinoside, and corticosteroids.
         Allogeneic stem cell transplantation is recommended as consolidation of Ph
          chromosome–positive ALL.
         Most maintenance therapy with methotrexate and mercaptopurine
 Sites: Reappear in bone marrow, the CNS, or the testes.
    Bone marrow relapse is particularly ominous.
    Although a new round of chemotherapy may induce a 2nd remission in 80 to 90% of children (30
     to 40% of adults), subsequent remissions tend to be brief.
    Only a few patients with late bone marrow relapses achieve long disease-free 2nd remissions or
    If an HLA-matched sibling is available, stem cell transplantation offers the greatest hope of long-
     term remission or cure
 When relapse involves the CNS, treatment includes intrathecal methotrexate
  (with or without cytarabine or corticosteroids) twice weekly until all signs disappear.
 Most regimens include systemic reinduction chemotherapy because of the likelihood of
  systemic spread of blast cells. The role of continued intrathecal drug use or CNS irradiation
  is unclear.
 Testicular relapse- painless firm swelling of the testis or on biopsy.
    If unilateral testicular involvement is clinically evident, the apparently uninvolved testis should
     undergo biopsy.
    Treatment is by irradiation of the involved testis and administration of systemic reinduction
     therapy as for isolated CNS relapse.
     Regardless of risk factors, the likelihood of initial remission is ≥ 95% in children
      and 70 to 90% in adults.
     Of children, 3/4 have continuous disease-free survival for 5 yr and appear cured.
     Most investigatory protocols select patients with poor risk factors for more intense
      therapy, because the increased risk and toxicity from treatment are outweighed by
      the greater risk of treatment failure leading to death
   Prognosis – age, WBC count, and cell type are the most important
    prognostic indicators
     Patients younger then 1 and greater than 13 have a poor prognosis
     If the WBC count is < 10 x 109/L at presentation, the prognosis is good; If the
      WBC count is > 20 x 109/L at presentation the prognosis is poor
     T cell ALL (more common in males) has a poorer prognosis than any of the B cell
      ALLs which have a cure rate of 70%
                Acute Myeloblastic Leukemia
 Malignant transformation and uncontrolled proliferation of an abnormally
  differentiated, long-lived myeloid progenitor cell results in high circulating
  numbers of immature blood forms and replacement of normal marrow by
  malignant cells.
 Disease rare in children; median age of onset of 50 yr.
   AML may occur as a secondary cancer after chemotherapy or irradiation for a
     different type of cancer
 Symptoms include fatigue, pallor, easy bruising and bleeding, fever, and
   symptoms of leukemic infiltration are present in only about 5% of patients (often as skin
 Examination of peripheral blood smear and bone marrow is diagnostic.
 Treatment includes induction chemotherapy to achieve remission and
  postremission chemotherapy (with or without stem cell transplantation) to
  avoid relapse
              Acute Myeloblastic Leukemia
 Acute myeloid leukemia (acute granulocytic leukemia) –
 classification depends upon:
   Bone marrow blast morphology-
       needed to differentiate ALL from AML but AML represents 20% of childhood
   Degree of cell maturation
   Cytochemical stains
   Immunophenotyping
   AML is divided into 7 different classifications:French American British
    (FAB) system
   m/c myelomonocytic
           M1 – myeloblastic without differentiation/ maturation 15-20%
            o The bone marrow shows  90% blasts and < 10% promyelocytes
            o The disease occurs in older adults
Note the myeloblasts and the auer
                                 Acute Leukemia
 M2 – myeloblastic with maturation (25-30%)
       The bone marrow shows 30-89% blasts and > 10% promyelocytes;
       characterized by an 8,21 chromosomal translocation
       This occurs in older adults

 M3 – hypergranular promyelocytic
         This form of AML has a bone marrow with >30% blasts
         Is more virulent than other forms ,characterized by a 15,17 chromosomal translocation
         Occurs with a medium age of 39
         The WBC count is decreased
         Treatment causes a release of the granules and may send the patient into disseminated
          intravascular coagulation and subsequent bleeding
         It is treated first with all-trans-retinoic acid (ATRA) which induces a complete response in 70%
          of cases and extends survival.
         APL patients are then given a course of consolidation therapy, which is likely to include
          cytosine arabinoside (Ara-C) and idarubicin.
   M3m – hypogranular promyelocytic
       The bone marrow has > 30% blasts , The WBC count is increased.
       Like the M3 type in treatment & DIC
 M2: Myeloblasts and
hypogranulated PMNs:
M3: Hypergranular promyelocytes
       AML – M3m
hypogranular promyelocytes
  AML-M4 Myelomonocytic
monoblasts and promonocytes
                           Acute Leukemia
 M4-Myelomonocytic-M/C 1/5
 M5 – acute monoblastic/monocytic leukemia (10-15%)
   >80% of the nonerythroid cells in the bone marrow are monocytic
   There is extensive infiltration of the gums, CNS, lymph nodes and extramedullary sites
   This form is further divided into
    o M5A - Poorly differentiated (>80% monoblasts)
    o M5B - Well differentiated (<80% monoblasts)
 M6 – erythroleukemia (DiGuglielmos disease) 5%
   This is rare and is characterized by a bone marrow having a predominance of erythroblasts
   It has 3 sequentially morphologically defined phases;
     o Preponderance of abnormal erythroblasts
     o Erythroleukemia – there is an increase in both erythroblasts and myeloblasts
     o Myeloblastic leukemia – M1, M2, or M4
   Anemia is common
 M7 - Acute megkaryoblastic leukemia 5%
     This is a rare disorder characterized by extensive proliferation of megakaryoblasts, atypical
      megakaryocytes and thrombocytopenia
Monoblasts: M5a
                        Treatment of leukemias
There are 2 goals:
            Eradicate the leukemic cell mass
            Give supportive care
 Types of therapy:
      Chemotherapy – usually a combination of drugs is used
           Induction: Cytarabine continuous infusion over 24 hrs for 7 days +
            daunomycin IV for 3 days
           75% experience remission (median 2 years) & 10-25% cured
        Bone marrow transplant & Radiotherapy- young pts
             o RT and transplantation can increase cure to 40-55%
        Immunotherapy – stimulate the patients own immune system to mount a response
         against the malignant cells
        Pts hospitalized for 4-6 weeks; pt often needs abx, multiple RBC and platelet
        All pts need consolidation chemo
               Prognostic factors
           Good                             Poor
 De novo leukemia              Leukemia with
   Not preceded by                myelodysplastic disorder
    myelodysplastic syndrome      Prior alkylating chemo
   Young age
                                  Advanced age
   Presence of cytogenetic
                                  High peripheral WBC
    abnormalities, t(15:17),
    t(8:21) and Inv 16            Presence of cytogenic
                                   abnormalities -5,5q, -7,+8
 Infection is leading cause of death
   Neutropenia, cachexia, immunosuppression
   Decontaminate gut w/neomycin + vancomycin
   Fever-panculture & broad spectrum abx
   Neupogen to increase WBC
 Bleeding is 2nd m/c
   Thrombocytopenia- Platelet transfusions maintain >20,000
   Anemia-PRBC hematocrit>25-30
   Stool softeners, suppress menses
   DIC in 10% (usually in promyelocytic)
     Caused by release procoagulants from leukemic granules
     Check PT, PTT, fibrinogen, d- dimer
 Anemia- exacerbated by marrow suppresive chemo
 Leukocytocis->100,000 may cause hyperviscosity (cerebral)
 Metabolic-
   Tumor lysis syndrome- hyperuricemia, hyperkaleia,
     TX: Hydration, alkalinization of urine, allopurinol
 Lactic acidosis in extremely severe illness due to huge leukemic cell
                             Hairy cell leukemia
 A chronic lymphoproliferative disorder with clonal neoplastic proliferation of
  a lymphocyte that related to memory B cells, activated B cells and preplasma
 Relatively rare leukemia of older men 3-5:1
   Mean age 52; 50% between 40-60
 Clinical Manifestations: weakness, weight loss, recent pyogenic infection,
  symptoms of splenomegaly (80%)
   Infiltrates spleen early in its course and presents with pancytopenia due to bone marrow
     failure and splenic sequestration

 Diagnoses: appropriate scenario and by ―hairy cells‖ on peripheral smear or
  BM; A special stain called TRAP is confirmatory as is flow cytometry

 Treatment:2-Chlorodeoxyadenosine – induce complete remission in 85%
    Chronic Lymphocytic Leukemia
 A neoplastic proliferation with accumulation of immune-
  incompetent lymphocytes within the bone marrow,
  peripheral blood, and lymphoid.
 Median age=65
 Comprises 30% or all leukemia
 Morphology: small mature lymphocytes with clumped
  chromatin and scant cytoplasm
 Manifestations:
   70% asymptomatic
   Generalized lymphadenopathy
   Fever, night sweats, fatigue, weakness
   Increased bleeding
   Frequent infections and exaggerated response to insect bites
     Both bacterial and viral 2nd to hypogammaglobulinemia and defects in cell
      mediated immunity
   More prone to autoimmune hemolytic anemia, ITP, pure red
    cell aplasia
 Increase in total # of lymphocytes in blood
 Peripheral smear: small, mature lymphocytes
 Flow cytometry: monoclonal proliferation that coexpresses
  CD 19 and CD 5.
                The Rai Staging System
 Stage 0-lymphocytosis alone
   Median survival>15 yrs
 Stage I- lymphocytosis with lymphadenopathy
   Median survival 9 yrs
 Stage II- lymphocytosis with liver/spleen involvement
   5 yrs
 Stage III lymphocytosis with anemia
   2 yrs
 Stage IV- lymphocytosis with anemia and thrombocytopenia
   Median survival 2 yrs

   Median survival expectation for a person with CLL- 8 yrs
 Observation if the patient is asymptomatic
 Oral alkylating agent chemo with or without prednisone is
  standard if the pt is symptomatic with fever, night sweats,
  fatigue, or massive splenomegaly
 Initiate treatment: presence of autoimmune hemolytic
  anemia, autoimmune thrombocytopenia, bulky
  lymphadenopathy, progressive hyperlymphocytosis, frequent
  bacterial infection