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					CM Heme Final Outline

L1: Childhood Anemia
Clicker Question #1
      -Which of the following is NOT a cause for anemia?
            A) Decreased RBC Production
            B) Increased RBC Destruction
            C) Decreased RBC Destruction
                    -you are KEEPING the RBC – so no anemia
            D) Vampire Bite (Acute Blood Loss)
            E) Chronic Blood Loss

Case #1: Introduction
       - 2mo female presents to the ER for fatigue, pallor and dehydration thought
       to be secondary to viral gastro. She improved with PO rehydration. The ER
       doc would like to send her home but he is concerned because he obtained a
       CBC which shows anemia. He has called you for consultation
              —CBC shows: WBC 12 Hb 9.5 Hct 31

Clicker Question #2
—What is a Normal Hemoglobin for a 2 month old?
     A) 13 – 20 - newborn
     B) 14 -18- adult male
     C) 12 - 16 – adult female
     D) 11 - 16 - 7yo – 12yo
     E) 9 - 14 - -lowest b/c at 2 months there is a physiologic nadir when HbA
                replaces HbF

Anemia
     -A hemoglobin that is 2 SD below the normal lab value for sex and age.

Case #1 :Physiologic Anemia of Infancy
       -An infants Hemoglobin slowly decreases over the first 6-8 weeks as fetal
       RBCs die.
       -Hb Rarely goes below 9
       -Triggers an increase in EPO and subsequent rise in hemoglobin
       -Does not need to be treated.
       -More severe in premature infants.
       -Our 2mo was discharged home and did very well.


Case #2: Introduction
       -2yo male presents to your office for fatigue and turning yellow. He has
       been otherwise well. The jaundice began 2 days ago and seems to be
       increasing. Mom states it started with his eyes and now seems to be his
       whole body.
What Other HPI/ROS Questions do we Need to ask?
       -Diet History
                 -How much milk does the child drinks?
                         Too much can lead to iron deficiency anemia
                -What kind of milk does he drink?
                         Goats milk doesn’t have folate
                 - Does he have any dietary restrictions such as being a vegan or not eating red
                meat?
                - Does he eat non-food substances? (Paper, dirt, paint chips  PICA)
       —Is he having any abdominal pain?
       —Are there any changes in his stool or urine? (melena, hematochezia, hematuria)
       —Any Vomiting? If so what color is it? (hematemesis)
       —If the patient is an adolescent female ask about heavy menses.
       —He eats a balanced diet. Drinks 2 glasses of whole cows milk a day.
       —No recent changes in diet
       —No fever, headache, dizziness, vomiting, changes in stool, abdominal pain, rashes, bleeding
       or bruising but he had dark urine today.
       —No recent Travel
       —Had a URI 2 weeks ago but no other recent illness.
—What medical history do you want to know?
       —Ethnicity – Middle Eastern
       —Allergies - None
       —Birth History – Term C/S for Breech Hyperbilirubinemia requiring phototherapy for 2
              days no jaundice since then.
       —Medical History – Hospitalized for RSV age 6mo
       —Surgical History - None
       —Medications – No home meds
       —Family History – No anemia, gallstones or spleen problems.
             A cousin 2x removed not blood related with a “Jaundice problem”.
       —Social History – Living with Mom and Dad. Watched by maternal
              grandmother during the day. No smoke. Pet Bunny named Coco.

Case #2 PE
       —T 37.6 RR 24 HR 150 BP 100/66 O2 99% RA
       —Gen – Active in no apparent distress. Pallor. Jaundice.
       —HEENT- Scleral icterus and pallor. Otherwise WNL
       —Neck – WNL
       —Resp – CTA Bilateral No wheeze
       —CV - Regular S1 S2 Grade 2/6 systolic ejection murmur. Good pulses in all 4 extremities.
       —Abd – S/NT/ND +BS No Hepatosplenomeagly
       —Ext – No Clubbing Cyanosis or Edema
       —Neuro – Non focal

—What Labs Do you want ?
       —WBC 14 Diff WNL Hb 5.9 MCV 80 Retic 11.9%
       —Na 139 K 4.5 Bicarb 21 BUN 6 Creat 0.8 BS 136
       —ALT and AST – WNL
       —Bili: Total – 11.4 Direct 0.2 Indirect 11.2
       —UA – 2+ blood otherwise WNL


How to classify Anemias
      —Red Cell Apperance
               —Normocytic                                           —Normochromic
               —Microcytic                                           —Hypochromic
               —Macrocytic

       —Physiologic Etiology
               —Decreased Production
               —Increased Destruction  JAUNDICE
               —Blood Loss

Clicker Question #3
      —What type of Anemia does out patient have?
           A) Normocytic with high Retic count
           B) Normocytic with low Retic Count
           C) Microcytic with High Retic count
           D) Macrocytic with high Retic Count
           E) He is NOT anemic let him go home and play with Coco

Differential for Normocytic Anemia
      —High Retic Count – bone marrow is responding
             —Acute or chronic blood loss
             —Autoimmune hemolytic anemia
             —Disseminated Intravascular Coagulation (DIC)
             —Hemolytic Uremic Syndrome (HUS)
             —Mechanical Heart valve
             —Membrane Disorders –Spherocytosis
             —Enzyme Deficiencies – G6PD, Pyruvate Kinase deficiency
             —Hemoglobin Disorders- Sickle cell
      —Low Retic Count- bone marrow is NOT working
             —Transient Erythroblastopenia of childhood.
             —Erythroid Aplasia
             —Hormone Deficiencies
             —Aplastic Anemia

Transient Erythroblastopenia of Childhood
      —A normocytic normochromic anemia
      —Presents in 1-4yo 2weeks -2months after a URI or GI illness with gradual
        onset of pallor.
      —Blood smear showss Low reticulocyte count.
      —Etiology is unknown.
      —Transient and self limited.

Blood Loss
      —Acute – Often there is an obvious and trauma related cause. The patient
      often presents with signs and symptoms of acute hypovolemia.
      —Chronic – GI Bleed or menstrual irregularities are often the source. Often
      mistaken for iron deficiency. Key to diagnosis is a thorough history and heme
      check stool.

Glucose 6 Phosphate Dehydrogenase Deficiency (G-6 PD)
      —Seen in 10% of African Americans. Also seen in Middle Eastern and South
      Asian
      —X- Linked Recessive
      —Deficiency decreases the oxidative protective mechanism of the RBC
      cell membrane.
       —Oxidative insult causes hemolysis
              - Medications (Asprin, Sulfa, primaquine and dimercaprol)
              - Fava beans***
             - Infection
       —Patients present with episodic anemia, jaundice and dark urine.
       —Blood smear shows normochromic normocytic anemia
       —Diagnosis is typically made on the newborn screen or with G6PD assay.
       —Treatment is supportive and avoidance of oxidative stressors

Spherocytosis
       —Autosomal dominant.
       —Deficiency of spectrin. – Rounded cel because it losing the membrane
       —Patients present with hemolytic anemia. Episodic pallor, jaundice or
            incidental splenomeagly.
       —Blood smear is normocytic normochromic with >10% spherocytes.
       —Osmotic Fragility test will be positive.
       —Coumbs test would be negative
       —Treatment is folic acid and monitoring
       —Spherocytes are destroyed almost exclusively in the spleen so splenectomy
       cures the anemia in pts with severe disease

Sickle Cell
       —Seen in 8% of the African American population and 2% of the
       Mediterranean population.
       —Sickle Cell trait is asymptomatic.
       —Hb SS, Hb SC, Hb Sβ
       —Typically diagnosed on newborn screen.
       —Smear shows normochromic sickled cells
       —Patients have chronic anemia, intravascular sickling and are at
            higher risk for infection from encapsulated organisms.
       —Episodic sickling leads to vaso-oclusive crisis.
       —Patients may present in pain crisis (abdomen, bone), with acute chest
       syndrome or with fever and infection.
       —Long term higher risk for impaired growth, avascular necrosis,
       congestive heart failure, ischemia, cholelithiasis and auto-splenectomy.
       —Patients are treated with folic acid and prophylactic penicillin
       —Pain crisis is treated with fluids and pain meds. If severe partial exchange
       transfusion is required.

Back To Case #2
       —Peripheral Smear: Normocytic anemia. NO Sickle cells or Spherocytes seen
       —G6PD assay: 1.4 IU/g hemoglobin (Nml 7-10)
       —DIAGNOSIS: G6PD
       —He was admitted during evaluation received 1 transfusion and extensive
       education on avoidance of oxidative triggers. He was discharged 2 days later
       and went home to Coco who missed him very much.

Case #3
- You are an intern on your first day of inpatient pediatrics. One of your patients is
a 3 yo male with autism who came to the hospital for increased behavior changes
and looking pale. The ED noted that he was anemic. He was admitted 1 hr before
your arrival. The H+P and workup are not done. Now you have to figure out what
work up to do and your differential before attending rounds.
—What Other HPI/ROS Questions do we Need to ask?
       —See past case for questions
       -When you walk into the patient room you find mom giving him bits of
       toilet paper which he promptly eats. When you ask her about it she states
       that “He loves to eat paper and it is the only thing that keeps him calm.” Mom states “He eats
       dirt and crumbs and anything else he can find.”
       —Diet : Mom states that because of his autism he is a “picky” eater. He does not drink any
       milk and only likes to eat hamburgers, French fries, pizza and easy mac.
       —Mom denies fever, headache, abdominal pain, vomiting, changes in stool, rashes, bleeding
       or bruising. She admits to pallor, fatigue and increased
       irritability.

—What medical history do you want to know?
       —Ethnicity – ½ African American ½ Hispanic
       —Allergies – Latex
       —Birth History – Normal SVD.
       —Medical History – Autism and delays.
       —Surgical History – Ear Tubes
       —Medications – he is supposed to be on an ADHD med but mom can’t get him to take it.
       —Family History – Mom has sickle cell trait. Biologic fathers history is unknown but mom’s
       boyfriend volunteers that he has asthma.
       —Social History – They live in the inner city in an apartment with mom’s boyfriend his
       sister and her 3 children. Mom is on welfare and does not work. Mom smokes. They have a
      cat named Boots

Case #3 PE
      —T 37.4 HR 135 RR 24 BP 98/64 O2 99% RA
      —Gen – Alert banging toys against the crib. Grunts but not using words and will not interact
      with you. (at baseline uses 5 words per mom)
      —Skin – Pale
      —HEENT – WNL
      —Neck – WNL
      —Resp – CTA Bilateral No wheeze
      —CV - Mildly tachycardic, no murmur, 2+ pulses
      —Abd – S/NT/ND +BS No Hepatosplenomeagly
      —Ext – No Clubbing Cyanosis or Edema


-What Labs/Tests do you want?
       - CBC = WBC 12 Diff WNL Hb 9 MCV 65

Differential for Microcytic Anemia
      —Iron Deficiency Anemia
      —Thalassemia
      —Lead Poisoning
      —Anemia of Chronic Disease
      —Sideroblastic Anemia

Iron deficiency Anemia
      —One of the most common heme disorders in children
      —Often caused by diet deficiency but may also be due to iron loss from
      bleeding.
      —Classic history includes exclusive or excessive milk intake.
      —Patients present with pallor, fatigue and irritability
      —Patients develop hypochromic, microcytic anemia.
      —Evaluation for Iron deficiency includes serum iron level(↓), total iron
      binding capacity (TIBC) (↑) and ferritin (↓)
      —Treat with a trial of iron in children with a history consistent with
      deficiency.
      —Treat with iron 2 months past return to normal Hemoglobin. If Hb not
      returning to normal then it is NOT iron deficiency and further work up
      should be done.

Clicker Question #4
      —When does an infant no longer have fetal hemoglobin?
           A) At Birth
           B) 1-3Months
           C) 3-6 Months
           D) 6-12 Months
                  -this is the age when thalassemia is going to show up b/c no
                  protective HbF
           E) There is no difference between fetal and adult hemoglobin


β-Thalassemias
      —Carried by 4% of people of Mediterranean descent. Also prevalent in the
      Asian and African American population.
      —Genetic mutation on chromosome 11.
      —2 β–globin genes. Both are present but there is decreased or absent
      production of β–hemoglobin. The severity of the anemia depends on how
      much β – hemoglobin is produced.
      —Diagnosed is made by hemoglobin electrophoresis which shows increased
      Hb A2 or Hb F. Target cells and Basophilic stippling seen on smear.

      —β-thalassemia minor/trait
            - One gene affected. clinically presents as a mild microcytic
            hypochromic anemia. Easily mistaken for iron deficiency. No therapy
            is necessary.
      —β-thalassemia intermedia
            - One gene affected or two genes incompletely affected. The patient
            still makes some β – hemoglobin but not as much as β - thalassemia
            minor. Clinical presentation is widely variable. Patients will have a
            moderate microcytic hypochromic anemia, bony deformities,
            pathologic fractures and growth retardation. They require only
            occasional to no blood transfusions.
      —β – thalassemia major
            – Both genes are affected. Little or no β – hemoglobin is produced.
            Patients present with severe microcytic hypochromic anemia and
            hepatosplenomeagly. Patients may also have bony malformations,
            jaundice, osteoporosis, cholelitihasis, cardiomeagly and cardiac
            dysfunction. Patients require regularly scheduled transfusions and are
            therefore at risk for Iron overload and require chelation therapy.
             Bone marrow transplant is curative. Without treatment these patients
             will die by age 10y

α - Thalassemia
      —Most common in southeast Asia, Malaysia and southern China
      —Genetic defect on Chromosome 16.
      —4 Genes control α – globin production. Severity of disease depends on how
      many genes are affected.
      —Diagnosed by genetic mapping. The responsible deletions are easily
      identified.
      —Silent Carrier
              – 1 α-gene lost. No clinical symptoms, but a carrier for α–Thalassemia
              trait.
      —Α-Thalassemia Trait (Minor)
              – 2 α-genes lost. Causes a mild microcytic,hypochromic anemia. No
              Therapy is required. 3-10% Hb Barts is seen on the Newborn Screen.
              Offspring at risk for severe Thalassemia.
      —Hemoglobin H Disease
              - 3 α-genes lost. Causes a moderate to severe microcytic hypochromic
              anemia. >10% Bart’s hemoglobin seen on Newborn screen. Excess β-
              hemoglobin forms tetramers (Hb H). Patients develop hemolysis,
              jaundice , cholelithiasis, bony abnormalities, growth retardation and
              hepatosplenomeagly. Transfusions are typically required.
      —α-Thalassemia Major – stillborn if you don’t tx w/ intrauterine transfusion
              - 4 α-genes lost. Results in Hydrops Fetalis. The fetus develops severe
              hypoxia, cardiac failure and pulmonary edema. Most infants are
              stillborn. Some fetus can survive the diagnosis is made early and they
              are given intrauterine transfusions. Hb seen in these infants is Hb H,
              Hb Barts and Hb Portland. If alive at birth the infant will have severe
              anemia, microcytosis and hypochromasia. PE will reveal severe
              hepatosplenomeagly, anasarca, pericardial effusions and pleural
              effusions. Patients must be supported with transfusions. Bone
              marrow transplant is potentially curative.

Lead Poisoning
      —Hypochromic, microcytic anemia with basophillic stippling of the RBC.
      —Lead levels >10 interfere with heme production
      —Risk factors are living in inner city areas, low socioeconomic class, Living
      in older homes (1960) and Pica.
       —Some children develop anorexia, vomiting and abdominal pain in addition
       to pallor and fatigue.
       —Can lead to a mild anemia often confused with iron deficiency or if severe
       (Level >100) it may lead to significant irreversible neurologic complications
       (encephalopathy, seizures, coma)
       —Treatment is Chelation with dimercaprol and EDTA.

Clicker Question #5
—Which of the following contains Lead?
   A) Some Folk Remedies
   B) Some Paints and Ceramic glazes
   C) Leaded gasoline
   D) B and C
   E) All of the above

Back to Case #3
       —Blood smear showed hypochromic, microcytic anemia with basophilic
       stippling
       —Lead Level 58
       —Diagnosis: Lead Poisoning
       —Treatment – Chelation therapy was started patients lead levels decreased
       and 5 days later he was discharged to follow up at the Lead clinic. The health
       department did a lead assessment in the home and repairs were made prior
       to patients discharge.

Case #4
       —A 15 Year old female presents to your office with a 2 month history of
       increasing fatigue and decreased activity. Mom states she used to play sports
       but started getting dizzy with activity and now just goes straight to bed after
       school

       —What Other HPI/ROS Questions do we Need to ask?
               -See other cases
       —The patient’s mom reports that she has been a strict vegan for 2 years and refuses to take
       vitamin supplements.
       —She admits to fatigue, dizziness and headache but otherwise ROS is negative. No Emesis
       change in stool or abdominal pain. Regular menses unchanged and described as “Light”
       lasting only 4 days.

—What medical history do you want to know?
       —Ethnicity – Caucasian
       —Allergies - amoxicillin
       —Birth History – Full term Repeat C/S.
       —Medical History - None
       —Surgical History – None
       —Medications – None
       —Family History – Mom has Asthma.
       —Social History – Patient lives with mom, dad, 2 older brothers and a dog named Mr. Fuzz.
       No smoke.

—Case #4 PE
       —T 37,4 RR 16 HR 110 BP 100/60 Ht 25% Wt 25%
       —Gen – Pale, Tired, Nontoxic, Answering all questions appropriately.
       —HEENT – Pale mucosal surface of eyelids. otherwise WNL
       —Neck – WNL
       —Resp – CTA Bilateral. No Wheezing
       —CV – Tachycardia. Regular. No Murmur
       —Abd – S/NT/ND +BS No Hepatosplenomeagly
       —Ext – Normal muscle strength DTR 2+ Brisk Capillary refill.
       —Neuro – CN 2-12 intact no deficits noted.

—Initial Labs
        CBC = WBC 14 Diff WNL Hb 6.4 MCV 98.7 Plts 173

Differential for Macrocytic
      —With Megaloblastic Marrow
               —Folate Deficiency
               —B12 Deficiency

       —Without Megaloblastic Marrow
               —Diamond Blackfan Anemia
               —Fanconi’s Anemia

Folate Deficiency
       —Dietary deficiency or medications
       —Patients with chronic hemolysis or malabsorption syndromes require
       supplementation.
       —Smear shows Normochromic macrocytic anemia with Macroovalocytes,
       Howell-Jolly bodies and hypersegmented neutrophils.
      —Patients may also have mild thrombocytopenia.
      —Patients present with Pallor, fatigue, malaise, glossitis, poor growth and
      recurrent infection.
      —Diagnosis is made by characteristic findings on smear and low serum folic
      acid level.
      —Treatment is with folic acid supplementation. 5-7 days into therapy you
      should see increased retic count if not then think B12 deficiency.

B12 Deficiency
      —Caused by dietary deficiency, illeal resection, parasitic infection or
      increased need (pregnancy)
      —Pernicious anemia = B12 deficiency due to deficiency of intrinsic factor
      leading to malabsorption of B12
      —Megaloblastic normochromic anemia
      —Smear shows Normochromic macrocytic anemia with Macroovalocytes,
      Howell-Jolly bodies and hypersegmented neutrophils.
      —Patients may also have mild thrombocytopenia.
      —Patients present with fatigue, pallor, glossitis, angular stomatitis, diarrhea,
      weight loss, parasthesias, peripheral neuropathies, ataxia and dementia.
      —Diagnosis is confirmed by a low serum B12 level
      —Treatment is with B12. Anemia typically improves after 2-4 days on
      therapy.

Back To Case #4
      —Peripheral smear showed Megaloblasts and a hypersegmented neutrophil
      —Serum folate 8.2 (Nml: 2-20)
      —Serum B12 <100 (Nml: 200 – 1000)
      —Diagnosis: Dietary Vitamin B12 deficiency
      —The patient was hospitalized and Started on B12. The hospital dietitian
      provided extensive counseling on nutritional requirements and
      supplementation.

Lecture 2: Sickle Cell Anemia
The Case
      -A Caribbean couple brings their 24 month old daughter to the ER for the 2nd
      time in 6 months because she refuses to bear weight on her feet. ROS shows
      no fever, infection or trauma. Medical history otherwise unremarkable. FH –
      both parents had siblings who died in childhood of infection; believe one had
      “sickle cell disease.” Previous records show normal labs except for slightly
      low hemoglobin.
      -On exam, she would not stand up and her feet were tender to palpation. The
      only other abnormalities were slight tachycardia and a palpable spleen tip.
      -Can all of this be related to an underlying diagnosis of sickle cell anemia?

History & Examination
      Preparing for Your SOAP Note
      -Present Illness
              -Neurologic symptoms, acute lethargy, increased weakness, fatigue, or
              dyspnea on exertion, should be documented.
      -Review of Systems
              -Specifically ask about symptoms of heart failure including edema,
              paroxysmal nocturnal dyspnea, orthopnea, and dyspnea with
              exertion.
      -Past Medical History
              -Previous hospitalizations
              -Previous transfusions, reactions, history of allo-antibodies, number
              of units, reasons for transfusions, and approximate dates
              -Treatment for iron overload?
      -Social History
              -Religious beliefs about transfusions and personal fears need to be
              explored
      -Physical Examination
              -Vital signs. Temperature, respiratory rate, blood pressure and pulse
      -Chest
              -Bibasilar rales
      -Heart
              -Neck veins, S3, increased murmur. Hyperdynamic precordium
      -Abdomen
              -Increase/decrease in size of liver or spleen.
      -Extremities
              -Edema
      -Neurologic
              -Document focal findings

What Are Usual Presenting Symptoms with Sickle Cell Anemia?
     -Anemia
     -Painful Crisis
     -Hand-Foot Syndrome
            -blocked small blood vessels, leads to deep bone pain (in one/both
            hands and/or feet), swelling and fever can occur. Swelling usually
            occurs on the back of the hands and feet and moves into the fingers
            and toes.
              -Dactylitis- swelling of the digits can be seen in pts w/ sickle cell
              anemia
              -This may be the first sign of sickle cell anemia in infants.
       -Splenic enlargement
              -filters out abnormal RBCs and grows large in SC. Leads to
              extravascular hemolysis - turnover of RBCs leads to anemia,
              sometimes jaundice.

What are other complications seen with Sickle Cell Disease? Memorize
      -Acute chest syndrome
      -Stroke
      -Osteonecrosis
      -Priapism
      -Proliferative retinopathy
      -Splenic infarction and sequestration
      -Leg ulcers
      -Gallstones
      -Aplastic crisis
      -Osteopenia—bone marrow hyperplasia
      -Nutritional deficiencies—folic acid, zinc, calories
      -Pneumococcal disease and sepsis
      -Placental insufficiency

Why is Sickle Cell Anemia Seen Most Commonly in Africans?
      -Confers selective advantage against death from malaria (Plasmodium
      falciparum)
              -Mediteranean, African descent
      -Autosomal recessive – 1 in 4 if both parents are carriers
      -Cell shape changes with low oxygen
      -How does this happen?

Why is the Red Cell Shaped Like it is?
      -Bi-concave disk
             -Flexible shape
      -Surface proteins & markers
             -rH
             -A,B,O
             -glycoprotein
      -Mostly a “bag of hemoglobin”

How is Red Blood Cell Structure Maintained?
      -Numerous membrane proteins
      -Spectrin scaphold inside cell
      -Band 3 protein
             -Binds ankyrin & spectrin
              -Binds hemoglobin

What is the Structure of Hemoglobin?
      -Composed of 4 subunits
              -2           -2 
      -Each has heme ring with a central Fe molecule
      -3-D structure change with low pH and O2 content of tissues

Oxygen Affects Hemoglobin Structure
      -Oxygen binding changes structure of porphyrin heme ring
      -Helical protein strand of the globin molecule is pulled.
      -“Conformation change” is communicated to other subunits

Hemoglobin Structure Influences Function
     -Protein-Protein contacts communicate conformational change in one
     subunit to others
     -This changes the conformation of the O2 binding site, making it a bit more
     receptive to O2
     -Positive Co-operativity: Change in one subunit is communicated to the next
     subunit, etc.

Tissue Metabolism Influences Hemoglobin Structure
       -Bohr Effect:
              -In high acid ([H+]) conditions, side chains of Hb take on hydrogen;
              changes Hb conformation
       -Result is LESS Hb oxygen content at given partial pressure of Oxygen
       -O2 leaves Hb & goes to tissues

How Does Normal Hemoglobin Differ From Sickle Cell Hemoglobin?
     -Single base substitution A for T at codon #6 of HBB gene on Chromosome 11
     -Substitutes hydrophobic Val for hydrophilic Glu
     -Changes protein properties

How Does HbS Differ From Normal Hb?
     -Exposed valine (in green) are hydrophobic
     -Create “sticky” areas that allow for “clumping” of HbS

How Does Mutation Change Properties of Hemoglobin Protein?
     -HbS has normal solubility in high oxygen conditions
     -Val6 causes a “sticky” spot on Hb molecule.
     -In low oxygen conditions, “sticky spot” exposed & deoxygenated HbS forms
     polymers
     -Result is twisting -helix of 14 sickle Hb
     -Not seen in sickle cell trait
How Does Polymer Formation Affect Cell Shape?
     -Strands of Hemoglobin – Attached to Band3 (anchored to cell) leads to
     extreme distortion of cell wall
     -Results in “Sickled Cell”

What Conditions Promote Sickling?
      -Dehydration
      -Deoxygenation
             -Altitude
             -Acidosis
             -Fever
             -Hypoxia

Why Does Sickling Cause Symptoms?
     -Normal morphology of cells lost
     -Sickle cells not compliant & block in small capillaries
     -Downstream blood flow blocked
             -Leads to ischemia and its sequelae

Sickle Cell affects the Spleen **TEST QUESTION** Know this!
        -Splenic enlargement
                -RBC sequestration
                -Infarction
                -Involution
                -Loss of immune function against encapsulated bacteria e.g.
                pneumococcus

Symptoms of Sickle Cell Disease
      -Anemia
            -Sickled RBC membranes rupture & Hb spilled
            -fatigue (tiredness), pale skin & nail beds, jaundice, & SOB
            -Marrow hyperplasia
            -Demonstrated by low hemoglobin (on CBC)
            -Bilirubin leads to pigmented gallstones

How does anemia relate to other symptoms associated with sickle cell?
     -Splenic filter & breakdown of RBC & Hb
     -Increased protein breakdown
     -Folate, zinc deficit
            SAM Cycle

What are effects of sickle cell on bone?
      -Osteonecrosis
              -Humeral & femoral heads
      -Hemosiderosis
      -Bone infarctions
       -Marrow hyperplasia
       -Osteomyelitis
             -Injury to GI tract and bone leads to seeding of injured areas with
             Salmonella

Skin Conditions Commonly Seen in Sickle Cell Cases
       -Chronic skin ulceration
              -25-70% adolescents w SCD
       -Maleolus
              -Common
              -After trauma
       -Due to change in NO
              -Related to release of Hb intravascularly
              -Tissue ischemia

Other Organ Damage
      -Chronic renal disease
              -Isothenuria
              -CRF
                     -May require dialysis
      -Sickle hepatopathy
      -Proliferative retinopathy
              -Progressive; major cause of visual morbidity. Treat the neovascular
              tissue before a vitreous hemorrhage occurs

Chest Wall Syndrome
      -An emergency!
      -Acute pain
      -Hypoxia
      -Lung infiltrates
      -Treatment
             -Exchange transfusion
             -Antibiotics
             -Oxygen/pain control
      -Chest X-ray on admission to the intensive care unit. It shows diffuse
      bilateral alveolar and interstitial infiltrates with decreased air entry

Sickle Cell Trait
       -Is it a benign condition?
       -Generally doesn’t confer increased risk
       -Caution with dehydration
       -Extreme heat
       -Case reports of death from “sickling” in individuals with trait

       Screening
            -Usually done at birth
                    -Must use definitive test
                    -Hgb Electrophoresis
             -Precipitation methods
                    -“Sickledex”
                    -For adult populations
                    -Positive if 10% HbS
                    -Cant tell trait from sickle cell disease

Laboratory Data
      -Complete Blood Count (CBC)
             -WBC (infection)
             -HgB (anemia)
      -Basic Metabolic Panel (BMP)
             -Kidney function (BUN/Cre)
      -Urinalysis
             -Specific gravity
             -Blood

How does Hydroxyurea work as a treatment for Sickle Cell?
     -Hydroxyurea
            -Only drug approved
            - NO
            - cGMP =  globin synthesis
                    -Leads to 2 Hb which don’t polymerize
            -Alters endothelial binding
            -Decreases leukocyte count

Patient-Related Data for Hydroxyurea
       -Raise Hb by ~ 1gm
       - transfusions
       - Painful crisis 50%
       - Mortality 40%
       - Hospitalizations
Exchange Transfusions
     -Exchange transfusions
            -Literally change the blood
            -Indicated in patients with
                    -acute neurologic events, severe pneumonia or pulmonary
                    infarction, acute arterial hypoxia, ophthalmological surgery,
                    priapism, high dose intravascular contrast studies, and
                    symptomatic anemia during pregnancy
            -Goal is 30-40% HbS; Hb 10
            -Improved symptoms and less hospital time

Indications for General Transfusion
      Absolute Indications
             -Acute neurologic event
             -Splenic sequestration
             -Severe pneumonia or pulmonary infarction
             -Severe anemia with cardiac decompensation
             -Acute arterial hypoxia
             -Aplastic crisis with severe anemia
             -Hyperhemolytic crisis with enlarging liver/spleen
             -Ophthalmological surgery
      Relative Indications
             -Symptomatic anemia
             -Hepatic sequestration
             -Leg ulcers refractory to conservative therapy
             -Priapism resistant to acute treatment or recurrent
             -Severe or prolonged pain episodes
             -Frequent pain episodes
             -Chronic respiratory insufficiency
             -High dose intravascular contrast studies
             -Surgery with general anesthesia.
             -Pregnancy

Management of Acute Chest
     -What orders might you want to consider?
           -Admission                                     -Nursing
           -Diagnosis                                     -Diet
           -Condition                                     -IV
           -Vitals                                        -Medications
           -Allergies                                     -Laboratory/Tests

Lecture 3: Hemoglobinopathies: The Thalassemias

The Case
      -JZ, is a 25 year old Canadian woman being seen for routine prenatal care.
      Her spouse, PS is a 34 year old professional tennis player of Greek origin.
      During history, she was unaware of any hematologic conditions in her family.
      Her screening laboratory revealed a mild microcytic anemia with Hb 9.8 g/L,
      MCV (mean corpuscular volume) 75m3. Subsequent Hb electrophoresis
      revealed elevations in HbA2 & HbF.
      -As her doctor, what does this mean and what needs to be done to care for
      her?

Hemoglobin Production Changes with Development
     -Combinations have different oxygen affinities
     -Fetal hemoglobin (HbF)
             -composed of 2 - & 2 γ-globin chains
     -HbA2
             -minor hemoglobin of adults
             -Contains 2 - & 2 δ-globin chains.
             -Normally 2 to 3% of all Hb
             - 4- 6% in most carriers of β-thalassemia.
             -The ζ (HBZ – zeta) and ε (HBE1-epsilon) genes normally expressed
             only in the embryo.
Thalassemia
      -Inherited anemias caused by defects in synthesis of one or more globin
      chain subunits of hemoglobin tetramer (HbA)
      --Thalassemia
             -decreased -chain production relative to β-chain production
      -β-Thalassemia
             -decreased β-chain production relative to -chain production

How are Alpha and Beta Globin Genes Structured?
      Alpha
            -Chromosome 16
            -2 genes on each
            -Usually disrupted by deletion
      Beta
            -Chromosome 11
            -One copy on each
            -Usual disruption by point mutation

What is the effect of the loss of a globin gene product?
      - &  produced in ~ 1:1 ratio
      -Excess of  &  leads to changes in formation of Hb tetramer.
      -Different combinations can form with ,  or other gene products

What are the genotypes & phenotypes of Alpha Thalassemia?
      -Deletion of one/both  genes on Chr#16
      -Clinical signs directly  as  # genes lost
      -Prevalence
              -Africans ~ 30%
              -SE Asians ~ 40%

How does the RBC change in alpha Thalassemia?
     -4 Tetramers (HbH)
             -Precipitate with dye
             -Oxidative stress
                    -anti-malarial drugs
                    -sulfonamides
     -More rapid turnover
             -RBC shorter lifespan
             -Microcytic, hypochromic anemia
     -Diagnosis
             -Hb electrophoresis or dye

How does -Thalassemia lead to Anemia?
     -Disruptions in gene transcription lead to absent (β0) or markedly  (β+) β-
     globin mRNA
      -β-thalassemia trait is asymptomatic
      -Disease seen in homozygotes or compound heterozygotes
             -More  than β chains
             -4 tetramers precipitate into “hemichromes”
             -Leads to red cell distruction

Hemichromes & Anemia
     -Oxidation of excess chains leads to precipitation
     -Binds to or modifies RBC membrane components
     -After precipitate, Hb disintegrates, releasing free Fe
     -Free Fe produces O2 radicals which oxidize RBC membrane, and leads to PS
     exposure
     -PS makes cells rigid, deformed and sticky, leading to removal

ß-thalassemia major: Cooley’s anemia
      -ß-thal major
             -no (homozyg ßo) or very little ß chain is made (homozyg ß+)
      -Anemia is seen
             -~ 6 months of life
             -When globin production normally shifts from predominantly  -chain
             to ß-chain.

What Tests To Confirm?
     -Peripheral blood smear
            -severe anisocytosis & poikilocytosis
            -target cells,
            -Elliptocytes
            -Teardrops
            -NRBCs
     -Hb electrophoresis
            -shows increased Hb F, increased HbA2, & variable amounts of HbA

Hemoglobin Electrophoresis
     -Confirms diagnosis
     -Ordered when microcytic (low MCV), hypo-chromic (low MCH) anemia
     detected on CBC
     -Electrophoresis then optical density scan to detect presence of abnormal Hb
     -Clinical implications

How much variation is there in Thalassemia patients?
     -A lot…
     -Most minor types demonstrate little in clinical symptoms
     -Both these guys play well with it…
     -More severe types require more aggressive treatment
This is our patient’s daughter CHIPMUNK FACIES asso. w/ thalessemia
       -What are the clinical implications of ß-thalessemia?
       -Red Cells Die Faster
              -Multiple transfusions required
              -Spleen enlarged
              -Folate deficiency
              - RBC production, but most cells destroyed before release
       -Erythroid Hyperplasia
              -Thickened bone marrow
              -Facial bone changes
              -Increased fracture risk & ectopic hematopoiesis

Anemia Leads to Iron Overload
     -Abnormal cells – hypersplenism
     -Increased erythropoietin
     -Massive medullary & extra-medullary hematopoietic tissue
     - GI iron absorption (Why?)
     -Frequent transfusions
     -All contribute to Iron overload – hemochromatosis

How Can You Determine Your Patient’s Iron Stores?
     -Serum Ferritin
            -Most common
            -Unreliable
            -<2500 mg/ml associated with inc survival
     -Liver Biopsy
            -Invasive
     -May not be accurate as some tissues take up iron preferentially

Cardiovascular Effects of Iron Overload
      -Cardiomyopathy
             -Major cause of death in beta-thallasemia
      -Venous thrombosis, pulmonary hypertension and embolism
             -Common
             -Membrane lipid oxidation, PS exposure activates platelets
             -Leads to clot formation and flow blockage

Endocrine Consequences
      -Iron Toxicity
             -Thyroid
             -Pituitary
             -Pancreas
             -Parathyroid
                     -Bone effects, osteoporosis & osteopenia
             -Testicular, ovarian failure
              -Delayed puberty

Bone Effects: Osteoporosis
      -Multifactorial
      -Chronic anemia
      -Hypoparathyroid
      -Hypogonadism
      -Ineffective erythropoiesis
      -All result in osteoporosis
              -Painful fractures

Treatment & Clinical Implications
      -Transfusion
             -Monitor Hb with CBC
             -Hb levels > 9
             -Venous port
      -Endocrine support
             -Hormone replacement
      -Avoid Iron Overload

Chelation Therapy
       -Deferoxamine
              -Most common
              -IV
       -Deferiprone
              -Oral
              -More effective for removal of myocardial iron
       -Combined synergy

Our Case
       -Patient had undiagnosed Beta thalessemia
       -Will need vigilance through pregnancy
       -Child will have risk of disease and will need close F/U
       -What might you do as her doctor?

Table 1: Commonly Encountered Thalassemias
Lecture 4: Management of Immune-Related Hemolytic Anemias
What is hemolytic anemia?
      -A condition where is not enough blood in the circulatory system.
      -Multiple etiologies:
             -Premature destruction
                     -Intrinsic
                     -Extrinsic
             -Production issues
             -Maturation defects

Anemia Summary
What do these fancy cells mean?
TOPICS FOR THIS LECTURE

     Autoimmune Hemolytic anemia
     ABO incompatibility


Autoimmune Hemolytic anemia:
     -Collection of disorders characterized by the presence of autoantibodies that
     bind to the patient’s RBC causing premature destruction of the RBC.

     -Incidence 1: 80,000
      -No racial predilection
      -Types



                                                                     TQ
                                                                     on this chart!




Primary Autoimmune Hemolytic anemia:            Primary
     -Warm Reactive AIHA:
            -Involves IgG.
            -Leads to extravascular hemolysis in the spleen, resulting in
            splenomegaly, jaundice, and anemia.
            - Pathophysiology:
                   -IgG antibodies coat erythrocytes and may fix complement.
                   -Immune clearance in the spleen.
                   -Does not lead to hemoglobinemia and hemoglobinuria since
                   cleared in the extravascular system.
     -Cold reactive AIHA:
            -If complement is activated, erythrocytes hemolyze in the
            intravascular system causing hemoglobinemia and hemoglobinuria.
      -Paroxysmal cold hemoglobinuria.
             -Common in children after viral like illness.
             -Causes intravascular hemolysis.
             -IgG antibodies.
      -Cold agglutin disease
             -Rare in children
             -Can occur after Mycoplasma infection.
             -IgM antibodies

Secondary Autoimmune Hemolytic anemia:
      -Is only one manifestation of a systemic illness. (ex lupus)
      -Pathophysiology
              -Autoimmune diseases
                      -Systemic Lupus Erythematosus
                      -Sjogren Syndrome
                      -Scleroderma
                      -Rheumatoid Arthritis
                      -Dermatomyositis
                      -Autoimmune Thyroiditis
              -Evans Syndrome
                      -AIHA with Idiopathic thrombocytopenia (ITP)
              -Malignancy
                      -Children:
                              -Hodgkin disease
                              -Leukemia
                              -Myelodysplasia
                      -Adults:
                              -Chronic lymphocytic leukemia
                              -Lymphoma
                              -Multiple Myeloma
              -Drugs: Forms a complex with the erythrocytes.
                      -Methyldopa
                      -Penicillins
                      -Cephalosporin's
                      -Tetracyclines
                      -Erythromycin
                      -Acetaminophen
                      -Ibuprofen
              -Infection (IgM autoantibodies)
                      -Viral illness, EBV, Varicella
                      -Bacterial: Mycoplasma pneumoniae, Rubella

AIHA Signs and Symptoms:
      -Weakness
      -Fatigue
      -Shortness of breath,
       -Dizziness
       -Pallor
       -Jaundice
       -Dark urine (Colors ranging red to black).
       -Fever
       -Abdominal pain

AIHA Physical Exam:
      -Skeletal abnormalities
      -Systolic flow murmur
      -Hepatosplenomegaly
      -Lymphadenopathy
*TQ* -Dark urine signifies hemoglobinuria indicative of intravascular
      hemolysis which is most suggestive of Cold-reactive AIHA.

AIHA Laboratory Evaluation:
      -CBC/Diff
      -Reticulocyte count
      -Peripheral blood smear
      -Urinalysis
      -Direct antiglobulin test
      -CMP
      -Haptoglobin




AIHA Treatment: not on test
      -Volume resuscitation
      -Avoid cold stimuli/ warming the environment:
             -Cold reactive AIHA
      -Corticosteroids
             -Warm reactive AIHA
      -PRBC’s transfusion
      -Splenectomy
             -Penicillin prophylaxis for twice a day for 2 years or life long.
      -Rituximab
             -Anti CD20 monoclonal antibody.
      -Danazol
      -Azothioprine
      -Cyclosporine
      -Cytotoxic agents
             -Vincristine, cyclophosphamide

Alloimmune Hemolytic Disease of newborn

Alloimmune Hemolytic Disease of newborn
      -Caused by destruction of the RBC’s of the fetus/ neonate by maternal IgG
      antibodies.
      -Only Maternal IgG caused HDN.
      -Types of HDN involves major blood groups
             -Rhesus (Rh)
             -A
             -B
             -AB – universal recipient
             -O – universal donor
             0Minor groups (Kell, Duffy, MNS)

Alloimmune Hemolytic Disease of newborn: Rh hemolytic disease
      -Individuals are identified as Rh – or Rh +.
      -This is based n the expression of the major D antigen on the erythrocyte.
      -It is the most common cause of alloimmune HDN despite the use of Rhogam.
      -Incidence 10.6/ 10,000. Unlikely to be seen in the first pregnancy.
*TQ* -Usually presents with jaundice in the first 24 hours of life.
*TQ* -Maternal sensitization:
               -Prior PRBC transfusion
               -Prior pregnancy with Rh + infant.

Alloimmune Hemolytic Disease of newborn: ABO hemolytic disease
      -Humans have 4 major blood types (A, B, AB, O)
      -At about 3-6 months of age, individuals naturally make A and/or B
      antibodies to the antigens found in the food and bacteria.
      -Hence ABO alloimmune HDN can occur in the first pregnancy.
      -Jaundice occurs in the first 24 hours of life.
      -Minor blood group antibodies develop in response to exposure to foreign
      RBC minor group antigens KELL, Duffy).
      -Disease ranges from mild jaundice to hydrops fetalis.

      -Diagnosis
            -Should be suspected when:
                  -Infant is Rh + and mother is RH –
               -A or B blood type infant born to Mother with O blood type.
-Labs:
         -Peripheral blood smear
         -Coombs test.

                                             -Direct: Positive direct coombs demonstrates
                                             the presence of maternal antibody on the
                                             neonatal RBC.
                                                    -Antibodies against IgG are prepared in
                                                    an animal and then mixed with the
                                                    patient’s blood.
                                                    -A positive test is when the patients
                                                    RBC agglutinates.
                                                            -if you’re looking for what is
                                                            causing these cells to lyse
                                             -Indirect: This is done to see if the patients
                                             serum contains antibodies that would cause
                                             agglutination of the other RBC’s. The Rh and
                                             ABO compatible RBC are mixed with the
                                             patient’s serum.




-Clinical presentation
       -Hyprebilirubinemia
              -Within the first 24 hours of life.
       -Anemia
       -Hydrops Fetalis
-Management
       -Assess the infant for respiratory or cardiac distress.
       -Anemia
       -Phototherapy
       -Exchange transfusions
-Labs:
       -Blood type
       -Coombs test: Positive Direct Coombs
       -CBC/Diff
       -Reticulocyte count
       -Bilirubin level
       -Type and Cross match.
Lecture 5: Management of Hemolytic Anemias Extrinsic to the
Erythrocyte – Splenomegaly, Infection and Micro-angiopathic
       -Problem outside of RBC

Topics to be discussed:
      DIC
      Malaria
      HSP
      Trauma to RBC
             -Drug associated hemolysis
      Oxidative injury
             -Methemoglobinemia

Case
       -6 year old male is seen in the ED with 2 day Hx of abdominal pain, low grade
       temperature and rash.


Disseminated Intravascular Coagulation

DIC
       -A condition resulting in consumption of clotting factors, platelets and
       anticoagulant proteins.
       -Results in widespread intravascular deposition of fibrin leading to tissue
       ischemia, necrosis and generalized hemorrhagic state and hemolytic anemia.
       -Clinical symptoms are primarily hemorrhagic but the initiating event is
       excessive activation of the clotting factors.
       -Consumes Protein C, Protein S and antithrombinIII, procoagulants resulting
       in deficiency of Factor V, Factor VII, prothrombin, fibrinogen and platelets.


       -Etiology:
              -Hypoxia
              -Endothelial damage.
              -Infection
              -Shock
              -Incompatible blood transfusion
              -Malignancy
              -Giant Hemangioma
              -Purpura fulminans
              -Pregnancy
              -Trauma
              -Snake bites
              -Kawasaki disease
              -Necrotizing entercolitis
       -Signs and Symptoms:
              -Usually accompanies a systemic illness
              -Bleeding from IV site or surgical site
              -Petechiae or ecchymosis
              -Tissue necrosis
              -Anemia
              -Infarction of tissues

       -Labs:
                -CBC/Diff
                -Factor II, V, VII
                -Elevated PT, PTT and INR
                -Blood smear:
                -Elevated fibrin split products
                -Elevated D-dimer
                -Burr cells, Helmet shaped cells

       -Treatment:
             -Treat the trigger than caused DIC (ex. DELIVER THE BABY!)
             -Restore normal hemostasis
             -Replacement therapy:
                     -Platelet transfusion
                     -FFP transfusion: Has clotting factors
                     -Cryoprecipitate: Had fibrinogen
                     -Correct the shock, acidosis, hypoxia
             -Role of heparin: Reserved with those with vascular thrombosis
             -Some adult studies have shown improved survival rate with use of
             Activated Protein C concentrate (APC) in those with DIC secondary to
             sepsis.


Malaria

Malaria:
      -It is an acute and chronic illness characterized by paroxysms of fever, chills,
      sweats, fatigue, anemia and splenomegaly.
      -Incidence: 300-500 million cases a year in developing countries.
      -Mortality: > 1 million deaths a year
      -1000 imported cases in the U.S
      -Etiology: Plasmodium Protozoa transmitted by the female Anopheles
      mosquitoes.
      -Four species:
               -P. falciparum (most fatal cases) **TQ**
               -P. malariae
               -P. Ovale
       -P. vivax
-Four pathologic processes are identified:
       1.) Fever: occurs when erythrocytes rupture and release merozoites
       into the circulation.
       2.) Anemia is caused by hemolysis, sequestration of the erythrocytes
       in the spleen and other organs and bone marrow suppression.
       3.) Immunopathologic events: Polyclonal activation resulting in
       hypergammaglobulinemia, and proinflammatory cytokines.
       4.) Tissue anoxia: Hypoglycemia and lactic acidosis.
-Clinical manifestation
       -Prodromal symptoms: 2-3 days prior.
               -HA
               -Fatigue
               -Anorexia
               -Myalgia
               -Pain in joints, abdomen and chest
       -Paroxysmal fevers
       -Vomiting, diarrhea, seizures,
-Diagnosis
       -Giemsa stained smears of peripheral blood.
               -Thick smear: Allows to scan large number of erythrocytes
               -Thin smear: Positive identification of the malaria species
       -A negative smear does not rule out the diagnosis.

-Treatment
      -Chloroquine sensitive
      -Chloroquine resistant
             -Quinine sulfate AND doxyclycine OR tetracycline OR
             clindamycin.
-Complications
      -Cerebral malaria
      -Renal failure
             -Blackwater fever: Clinical syndrome of severe hemolysis,
             hemoglobinuria and renal failure.
      -Pulmonary edema
      -Hypoglycemia
      -Thrombocytopenia
      -Splenic rupture
      -Algid malaria:
             -Overwhelming infection, hypotension, hypothermia, rapid
             weak pulse, shallow breathing, pallor, vascular collapse.
             -Death in few hours.
-Prevention
      -Chemoprophylaxis: Chloroquine, Mefloquine, Doxycycline
      -DEET
      -Protective clothing
Oxidative injury to RBC: Methemoglobinemia

Methemoglobinemia
     -Oxidation of heme iron from ferrous Fe+2 to Ferric Fe+3 state leads to an
     altered hemoglobin with decreased ability to bind oxygen.
     -Increasing incidence is seen with the use of “poppers” (nitroglycerin) in
     adolescents and young adults to increase sexual intensity.
     -Causes:
            -Nitrates/ Nitrites
            -Acetaminophen
            -Dapsone
            -Sulfonamides
            -Anesthetics ( the “caines”)
     -Methemoglobin results:
            -Cyanosis if > 10%
            -Death if > 70%
     -Treatment
            -Vitamin C
            -Methylene blue
            -Hyperbaric oxygen


Trauma to RBC: Drug associated hemolysis

Drug induced immune hemolytic anemia
      -When a medication triggers the body’s immune system to attack RBC’s.
      -Rare in children
      -Drugs:
             -Cephalosporins (a class of antibiotics) -- most common cause
             -Dapsone
             -Levodopa
             -Levofloxacin
             -Methyldopa
             -Nitrofurantoin
             -Nonsteroidal anti-inflammatory drugs (NSAIDs)
             -Penicillin and its derivatives
             -Phenazopyridine (pyridium)
             -Quinidine
      -Labs:
             -CBC/Diff
             -Reticulolyte count
             -Total and direct bilirubin
      -Treatment:
             -STOP the medication
              -Supportive
              -Transfusions if profound anemia is appreciated.



Henoch-Schonlein Purpura

HSP- palpable purpura after URTI
      -Also known as anaphylactoid purpura.
      -A common vasculitis of small vessels with cutaneous and systemic
      complications.
      -Most common nonthrombocytopenic purpura in children.
      -Etiology is unknown.
      -Most occur between the ages of 2-8 years and during winter months.
      -Males: Females = 2:1
      -Clinical manifestation:
             -Low grade temperature
             -Fatigue
             -Rash
                     -Palpable purpura
                     -Predominantly noted on Buttocks and LE
             -Angioedema which precedes the rash
             -Abdominal pain: Heme positive stools, Intussusception
             -Arthritis: Knees and ankles
             Renal involvement: Hematuria, proteinuria,
      -Diagnosis
             -Clinical diagnosis.
             -When not typical, biopsy is confirmatory
      -Labs:
             -Thrombocytosis
             -Leukocytosis
             -Elevated ESR
             -Anemia (due to blood loss)
             -Coags
             -Negative ANA, ANCA, RF
      -Treatment:
             -Symptomatic care: Self limiting vasculitic disease in 4-6 weeks.
                     -Hydration
                     -Bland diet
                     -Pain control
                     -Corticosteroids with intestinal complications
                     -Hydrostatic reduction.
      -Complications:
             -Nephrotic/ Nephritic syndrome (less than 1%)
                    -UA and renal function should be assessed at presentation and
                    for 6 month F/U. If persistent finding, peds nephrology referral
                    must be placed.
             -Testicular torsion secondary to scrotal swelling.
                    DO NOT MISS – CHECK IN ALL MALES WITH ABDOMINAL
                    PAIN!


Lecture 6: Management of Hemolytic Anemias: Disorders of
Erythrocyte Membrane and Enzymopathies
      -Problem w/I RBC
Topics to be discussed:
      Hereditary Spherocytosis
      Elliptocytosis
      Paroxysmal Nocturnal Hemoglobinuria
      Hemoglobinopathies
             Sickle cell disease, Thalassemias
      G6PD
      Pyruvate Kinase deficiency


Hereditary Spherocystosis

Hereditary Spherocystosis
      -Most common congenital hemolytic anemia
      -Incidence 1/5000
      -Inheritance:
             -Autosomal dominant
             -Autosomal recessive
             -25% no inheritance pattern
*TQ* -Causes a structural abnormality of cytoskeleton proteins, spectrin,
      ankyrin, band 3. – lose biconcave structure
      -Spherocytes are more rigid and cannot travel through the splenic sinusoids.
      -Presenting signs and symptoms
             -Asymptomatic
             -Fatigue
             -Pallor
             -Tachycardia
             -Dizziness
             -Predominantly: Jaundice and anemia in the newborn period.
      -Labs
             -CBC/Diff
                     -Anemia (Hgb 6-10)
             -CMP- liver jazz!
                     -Elevated Total Bilirubin
              -Reticulocyte count
                      -Elevated
              -Direct Bilirubin
              -Osmotic Fragility Test – do it after 6 months so there is no fetal
                                         hemoglobin left!
              -Gel electrophoresis
       -Complications
              -Cholelithiasis: bilirubin stones
       *TQ* -Susceptible to aplastic crisis:
                      -Parvovirus B19.
              -Splenectomy: Asplenic patient should receive these
              immunizations.
                      -so RBC don’t get stuck!!
                      -Pneumococcal Vaccine
                      -H. Influenza Vaccine
                      -Meningococcal Vaccine
              -Bone marrow failure secondary to profound anemia. Can lead to high
              output heart failure, hypoxia and cardiovascular collapse and death.
       -Differential Diagnosis
              -Immune hemolytic anemia
              -Thermal injury
              -Clostridial septicemia
              -Wilson’s Disease
       -Treatment
              -Phototherapy
                      -Bilirubin blanket (Wallaby)
                      -Single/ Double overhead phototherapy light
                      -Triple therapy: Double lights + bilirubin blanket
                      -Partial exchange transfusion
              -PRBC transfusion
              -Partial/ Complete Splenectomy
              -Vaccines
       **TQ**-PCN prophylaxis:
                      -Less than 5 yrs: 125 mg bid
                      -Greater than 5 yrs: 250 mg bid
       Pathologic Jaundice
              -jaundice w/I the first 24 hours of life!!! BAD!


Elliptocytosis
       -Elliptocytosis
              -Most commonly seen in West Africans.
              -Inheritance: Autosomal Dominant
       **TQ**-Defects in the spectrin gene.
              -These spectrin mutations has been found to provide some resistance
              to malaria infection.
             -Varies in severity:
                    -No symptoms
                    -Neonatal Poikilocytosis (shape variation) and hemolysis
                    -Hereditary Pyropoikilocytosis (HPP)- changes shape w/ heat
             -Signs and Symptoms
                    -Newborn jaundice
                    -Anemia
                    -Splenomegaly
                    -Cholelithiasis
                    -Aplastic crisis
             -Labs:
                    -CBC/Diff
                            -Anemia (Hgb 6-10)
                    -CMP
                            -Elevated Total Bilirubin
                    -Reticulocyte count
                            -Elevated
                    -Direct Bilirubin
                    -Blood smear.
             -Treatment
                    -No treatment is needed if there is no evidence of hemolysis.
                    -Patients with chronic hemolysis should receive Folic acid 1 mg
                    daily to prevent secondary folate deficiency.
                    -Splenectomy (generally curative)
                    -PRBC transfusion


Paroxysmal Nocturnal Hemoglobinuria

Paroxysmal Nocturnal Hemoglobinuria
      -Reflects an acquired abnormality in the marrow stem cells that affects each
      blood cell lineage.
      -The two membrane components of the complement system are missing:
             -Decay accelerating Factor( DAF)
             -Homologous restriction Factor( HRF)
      -These missing factors make the cells more susceptible to complement.
      -Varying degree of intravascular hemolysis.
      -Rare disorder in children.
**TQ**-Nocturnal and morning hemoglobinuria is a classic finding.
      -Labs
             -CBC/Diff
                     -Anemia (Hgb 6-10), Leukopenia, Thrombocytopenia
             -CMP
                     -Elevated Total Bilirubin
             -Reticulocyte count
                     -Elevated
             -Direct Bilirubin
             -Blood smear.
             -Coombs Test
                     -Negative since the cells are lysed before they agglutinate
             -Assays for DAF and HRF by flow cytometry.
             -Hemosiderinuria.
       -Complications:
       **TQ**-Thrombosis / Thromboembolic events:                NO CLOTTING
                     -Abdomen, Brain
             -Pancytopenia
             -Thrombocytopenia
             -Leukopenia
       -Treatment:
             -Splenectomy is not indicated.
             -Prednisone (2 mg/kg/24 hrs) has been used to treat acute hemolytic
             episodes.
             -Anticoagulation therapy may be indicated in thrombotic events.
             -Iron therapy
             -Antithymocyte globulin, cyclosporine, Growth factors (erythropoietin
             and granulocyte colony stimulating colony factor) are used to treat
             bone marrow failure.
             -Eculizumab, humanized monoclonal antibody against complement
             C5.
             -Bone marrow transplant.


Hemoglobinopathies
Sickle Cell Disease

Thalassemias

Hemoglobinopathies
     -Hemoglobin is a tetramer made with 2 pairs of globin chains.
     -Abnormalities in any of these proteins is referred to as Hemoglobinopathies.
     -The Hgb pattern changes through fetal development.
     -HbA, HgA2, HgF is most commonly seen.


Sickle Cell Disease
       -Hb A is the result of a single base pair change (thymine for adenine) on the
       β globin gene which encodes valine instead of glutamine.
       -Located on Chromosome 11.
       -Sickle Cell Anemia: Homozygous HbS, when both the β globin genes have the
       sickle cell mutation.
       -Sickle cell disease: Refers to
         -Individuals with sickle cells anemia
         -Heterozygotes:
                -One globin chain: HbS
                -Other globin chain: HbC, Hb D,
-It is the most common genetic disease indentified through the state
mandated newborn screening.
**-Average lifespan of sickle RBC is 15-50 days.** Normal 120 days
-Average lifespan in the U.S is 42 years in males and 48 in females.
-In Africa, average lifespan is 5 years of age.
-Incidence: 1/2647 births
-Occurring in African American couples: 1/396 births
-Asian: 1/16,000
-Hispanics: 1/36,000
-Signs and Symptoms
         -Dactylitis- swelling BILATERALLY of hands – very painful
                -Often the first presentation of sickle cell disease.
                -50% present by 2 years of age.
                -Usually Bilateral.
                -Unilateral dactylitis: Osteomyelitis
                -Treatment:
                        -Pain relief/ NSAIDs
         -Anemia and reticulocytosis present at 2-6 months of age.
         -Pain Crisis:
                -Most common feature of SCD
                -Most common reason for hospitalization.
                -Treatment:
                        -IV hydration
                        -NSAIDs
                        -Opoid analgesics
         -Splenic Sequestration:
                -The spleen becomes massively enlarged and engorged in
                blood.
                -Usually should be suspected with splenomegaly and
                worsening anemia.
                -Treatment:
                        -IVF’s
                        -Blood products
                        -Splenectomy after the acute episode.
         -Acute Chest syndrome- Looks like pneumonia
                -Defined as development of new infiltrate with fever, chest
                pain, tachypnea, hypoxia.
                -Causes: Infection, infarction, atelectasis or fat embolism from
                the bone marrow.
                -Treatment:
                        -Oxygen
                        -IVF’s
                             -Transfusions
                             -Antibiotics
               -Aplastic Crisis:
               *TQ* -Occurs secondary to Parvovirus B 19.
                     -Characterized by low Hgb, Low reticulocyte count and low
                     serum bilirubin.
                     -The low reticulocyte count differentiate aplastic crisis from
                     worsening anemia in sickle disorders.
               -Stroke:
                     -Peak incidence between 5-10 years.
                     -CT of MRI is diagnostic.

                     -Acute treatments:
                            -Exchange transfusions
                            -Hydroxyurea to prevent recurrence.
                            -Moya moya Syndrome – CTMRA shows puff of smoke
               -Priapism
                     -Prolonged and painful erection.
                     -Seen in 10% of males.
                     -Management:
                            -IVF’s
                            -Pain control
                            -Transfusions
                            -Aspiration of the corpora cavernosa and irrigation with
                            dilute epinephrine.
               -Fever:
                     -Functional asplenia by 5 yrs of age.
                     -Bacterial sepsis is the most common cause of morbidity and
                     morality.
                     -They are at increased risk of infection on encapsulated
                     organisms such as streptococcus pneumoniae,
                     Haemophilus influenza Type B.
                     -They are also at increased risk for salmonella sepsis.
                     -Parvo B 19
                            -Limits the production of reticulocytes.

       -Diagnosis
             -Hemoglobin electrophoresis- see the variation of hemoblob pt has
             -Treatment:
                   -Supportive
                   -Bone marrow transplant.


Sickle Cell trait
       -They have normal CBC/Diff, blood smears.
       -Life expectancy is normal.
     -No medical issues except with physical exertion of low oxygen.


Thalassemia
     -Autosomal recessive genetic disorders of the globin chain production.
     -Imbalance between the α and β chains.
     -Types:
            -β- Thalassemia: Complete or partial absence of the β globin gene.
            α – Thalassemia: Complete or partial absence of the α globin gene.
     -β - Thalassemia
            -Three categories:
                   -Minor:
                         -Heterozygotes.
                         -Mild to no anemia
                         -Hypochromia, Target cells, basophilic stippling can be
                         noted.
                         -Finding Hb A2 > 3.5% is diagnostic.
                   -Major:
                         -Cooley anemia.
                         -No β globin chain production.
                   **TQ**-The α chain precipitate into Heinz bodies.
                         -Pallor, Irritability, hepatosplenomegaly, growth
                         retardation, jaundice.
                         -Chipmunk facies.
                         -All Hb F on electrophoresis.
                   -Intermediate:
                         -Some normal β globin chain production.
                         -Milder symptoms as opposed to Cooley’s anemia.

     -α - Thalassemia
            -Four types:
                   -α - Thalassemia Trait:
                          -One locus, asymptomatic, no hematologic
                          abnormalities
                   -α - Thalassemia minor:
                          -Two loci, asymptomatic, MCV low, mild anemia
                   -HbH:
                          -Three loci, Moderate to severe hemolysis
                   -Hb Bart’s:
                          -Four Loci, death in utero, Hydrops fetalis.
            -Signs and Symptoms
                   -Profound weakness
                   -Cardiac decompensation.
                   -Typical facies
                   -Pathologic bone fractures
                   -Hepatosplenomegaly.
                  -Jaundice
             -Management
                  -Frequent transfusions
                  -To monitor for transfusional hemosiderosis.
                         -Frequent Iron levels.
                  -Bone marrow transplant
                  -Folate supplementation.


G6PD
       -Glucose 6 Phosphate dehydrogenase deficiency.
       -Inheritance: X linked recessive
       -Measurement of the enzyme is diagnostic
       -Affects 200 million individuals worldwide.
       -Heterozygous females are resistant to falciparum malaria.
       -Two clinical syndromes:
              -Episodic hemolytic anemia: secondary to infection, medications, fava
              beans.
              -Chronic hemolytic anemia.
       -Usually develops symptoms (jaundice, hemoglobinuria) 24-48 hrs after
       ingestion of a substance that has oxidative properties (Aspirin,
       sulfonomides, antimalarials, Chloramphenicol, fava beans)
       -The extent of hemolysis varies with the inciting agent:
              -Amount ingested
              -Severity of enzyme deficiency.
       -Labs
              -CBC/Diff
                      -Low Hgb and Hct
              -Blood smear
                      -Heinz bodies
              -Total and Direct bilirubin
              -Diagnosis is measurement of G6PD enzyme level.
       -Management
              -Prevention
              -Supportive therapy:
                      -Blood transfusions
                      -Discontinuation of the oxidative substance.


Pyruvate kinase Deficiency
       -Seen in individuals with homozygous deficiency of the enzyme.
       -Mutations noted in the PKLR gene found on chromosome 1q21.
       -Autosomal recessive.
              -Marked decreased in PK enzyme
              -Production of an abnormal enzyme
       -Low ATP, pyruvate and NAD
      -Clinical manifestation
             -Varying from severe neonatal hemolytic anemia to well compensated
                     hemolytic anemia in adulthood.
             -Pallor, jaundice, fatigue and splenomegaly.
      -Labs:
             -Elevated Reticulocyte count
             -Decreased Hgb
             -Marked reduction in PK activity.
      -Treatment
             -Exchange transfusions
             -Splenectomy if requiring frequent transfusions


Lecture 7, 8 and 9: Hodgkin’s, Non-Hodgkin’s Lymphoma and
Multiple Myeloma aka. Lymphoid Malignancies
Outline
      I. Hodgkin’s Lymphoma
              -Case 1
              -Case 2
      II. NonHodgkin’s Lymphoma
              -Case 3
              -Case 4
      III. Multiple Myeloma
              -Case 5
              -Case 6

Lymphoma – Overview
     -Lymphoma is a malignancy that originates in the lymphoreticular system.
           -It develops for the most part in lymph nodes as depicted below.
           -Extra-nodal disease can occur as well in such areas as the bone
           marrow, GI tract, skin, liver or lung.
           -CNS lymphoma is also a known but albeit rare entity.
           -Systemic disorder of immune/lymph system (which is mostly housed in
           the nodes)
Overview
      -Majority of cell types are B cell in origin
      -Today’s lecture will concern itself w/ B cell malignancies predominantly
      -T cell lymphomas make up a small percentage of NHL
      -Lymphomas develop from cells of the immune system at various phases of
      their development and maturation.
               -Normal immune cells are programmed to grow and die based on an
               antigen.
               -If they acquire a mutation that prevents them from dying in the
               normal, programmed way, a lymphoma is potentially born.

Differential Diagnosis for Lymph Adenopathy
       -Mononucleosis Syndrome
               -CMV, EBV, Toxoplasmosis, HIV
       -Tuberculosis
       -Sarcoidosis
       -Systemic Lupus Erythematosus
       -Monocytic Leukemia (chloroma)
       -Solid tumors (poorly differentiated carcinoma)

Lymphomas
     -Clinical Aspects
            -When to suspect lymphoma
                   -Persistent nodal enlargement x 4-6 weeks
                   -No identifiable infectious source
                   -Nodes should be nontender, ~2 cm or greater
                   -Presence of B-symptoms (fevers, nightsweats, weight loss like
                   10% of body weight!!)
                   -Presence of any autoimmune disease
                   -Chronic immuno-suppression (transplant)
             -Medical emergencies associated with NHL
                      -Superior vena cava syndrome (mediastinal)
                              -engorement of blood vessels
                      -Airway obstruction
                      -Epidural cord compression (retroperitoneal)
                      -Hyperviscosity (IgM)
                              -stoke-like syndromes/ neurological deficits
                      -Tumor lysis syndrome (hyperuricemia)
                      -Hypercalcemia (T-cell lymphomas)
             -Initial work-up should include:
                      -Full staging CT or PET scan- CT scan for staging
                      -CBC and blood smear
                      -Chemistry with liver function, urate and LDH
                      -Serum protein electropheresis with immunofixation
                      -Bone marrow biopsy and aspirate
                      -Lumbar puncture (special cases like neurological deficits)
                      -Biopsy of whole node or core needle – NO FNA because high
                                                             FN rate
                      -Grading (pathologist)
                      -Flow cytometry to define monoclonality and
                      immunophenotype
                      -Immunohistochemistry
                              -Important for treatment with antibodies
                      -T cell receptor gene rearrangement – remember more B cell
                      predominant so this isn’t done as much!
                      -Cytogenetics & FISH (translocations)


Hodgkin’s Lymphoma
      -Reed-Sternberg cell proven in 1999 to be the cell of origin OWL EYES,
      POPCORN
            -Pathonomonic for Hodgkin’s lymphoma
      -Make up very small percentage of total cells in the lymph node
            -1 or 2 RS cells in a peripheral smear


Case 1 – Initial Presentation
      -18 yo VT freshman presents to student health with painless swelling in his
      neck
      -No major medical illnesses
      -No childhood illnesses
      -No family history of malignancy
      -History of strep throat last year

      Questions:
            -What questions should we ask this patient?
            -What physical exam findings should we note?
            -What diagnostic tests should we order?
      Presentation:
            -You discover the patient has no sick contacts, owns no cats, and has
            no sex partners
            -He is fatigued and has not been eating well. Weight is down 5-10 lbs.
            -He has very mild “scratchy” throat without fever.
            -He tells you he had chest pain after drinking at a frat party
                    - (old wives tale!)
      Exam Findings:
            -On exam you note bilateral, anterior cervical adenopapthy 3-4cm in
            diameter
            -The nodes are nontender and moveable
            -His tonsils are slightly enlarged w/o pus
            -Nothing further abnormal found on exam
            -His rapid strep is normal
            -His monospot is negative

What diagnostic tests should be ordered next?
    -When suspecting a lymphoma – always get ample tissue, not a fine needle
    aspirate - FNA will miss it! Has a high false negative rate!
    -Whole node is preferred! – b/c low % of Reed Sternberg Cells
    -Send it for flow cytometry to determine clonality and immunophenotype
    -Nodular sclerosing is the most common subtypes

      Once Hodgkin’s disease is diagnosed staging is often done with CT or PET
      imaging
      Stage determines treatment intensity and prognosis
      -Chest X-Ray
             -~ 1/3 of the mediastinum is enlarged with a nodal mass
             -This would be considered “bulky” and would require more intensive
             therapy
      -Bone marrow biopsy is performed
             -If involved, this is a poor prognostic sign

-Ann Arbor Staging - **KNOW THIS!**
Staging
      -B symptoms
             -Caused by immune mediated cytokines and include:
                   -Fevers (usually episodic)
                   -Night sweats (soaks bedclothes, sheets)
                   -Unintentional weight loss (>10% body weight)
      -Their presence portends worse prognosis

Additional Testing
      -Besides CT/PET imaging and bone marrow biopsy patients need:
             -CBC with differential
             -Chemistry panel with albumin, liver studies and sedimentation rate
             -Presence of anemia, low albumin or high sedimentation rate
             portends worse prognosis

Case 1
         -Our patient has no classic b symptoms
         -He has involvement of the mediastinal and cervical lymph nodes w/o bone
         marrow involvement  Stage 2a
         -CBC and chemistry studies are normal
         -Sed. Rate is normal

Prognosis
     -Presence of anemia, low albumin, high sed rate, b symptoms, older age, high
     stage, extra-nodal dz – all portend worse prognosis
     -Graph shows outcome at 7 years for patients with different # risk factors

-The patient begins chemotherapy with adriamycin, vinblastine, bleomycin and
dacarbazine (ABVD)
-He achieves a complete remission
-He receives radiation to the large mediastinal mass and adjacent lymph nodes


Treatment of Hodgkin’s Lymphoma
      -Chemotherapy is given over a period of 3-6 months
      -If patient achieves remission, then radiation is given to nodal regions
      affected and adjacent nodes


Case 1:
         -The patient was followed every 3 months with exam, labs and periodic
         imaging
         -18 months after achieving remission, he felt an enlargement under his right
         arm – REBIOPSY!!
         -Biopsy showed nodular, sclerosing, classic Hodgkin’s similar to in his neck
         -He is restaged with scans and bone marrow
       -He has no B symptoms
       -His CBC and chemisties are again normal
       -He is referred to a large, university center for second opinion
       -Begins therapy with ifosfamide, carboplatin and etoposide (ICE)
       -He achieves remission after 3 cycles
       -His own bone marrow stem cells are harvested
       -He receives busulfan, etoposide, cytarabine and melphalan (BEAM) followed
       by stem cell rescue
       -He remains in remission for the rest of undergrad and grad school after
       which he leaves your practice, healthy and well

Case 2 –remember there is a bimodal age distribution Young Adults and Older Adults
-Initial Presentation
        -88 yo former VT professor presents with painless swelling in his inguinal
        area
        -What are some questions we should ask this gentleman?
        -You discover he has a chronic dermatitis for which he uses topical steroids
        -He has a history of prostate cancer and received radiation 7 years ago
        -He has lost 15 lbs and is having nightsweats
        -He takes lipitor and and ACE inhibitor
– Exam
        -Nodal mass in the right inguinal area is 6cm, with associated lymphedema
        -No hernia
        -No redness, skin breakdown or pain
        -No skin lesions
        -Foreskin without ulceration
– Diagnostics
        -What further studies should be done at this point?
        – Work Up
               -CT scan of the body shows large nodal mass in the inguinal area on
               the right (9x10cm) – can jump to this 1st b/c of age – don’t have to
                                      think about cumulative effect!
               -Iliac and para-aortic lymph nodes are enlarged to 4cm
               -Spleen is enlarged to 20 cm
               -Biopsy shows mixed cellularity, classic Hodgkin’s lymphoma
               -CBC is significant for hgb 10.6, wbc of 15,700 – poor prognosis
               -ESR is elevated – poor prognosis
               -Albumin is low at 2.6 – poor prognosis
- Staging
        -What stage is the patient?          Stage 2 BS b/c all BELOW diaphragm
        -What are some adverse features seen?

- Treatment
       -Patient begins chemotherapy at reduced doses
       -He tolerates it very poorly with hospitalizations for infections and
       transfusions
       -After a couple months of chemotherapy, he has a partial remission
       -Radiation is used to treat remaining disease
       -Disease remains in remission for several months
       -Develops contralateral inguinal nodal mass
       -Biopsy reveals Hodgkin’s lymphoma similar to prior
       -Restaging scans show disease in pelvic, abdominal and thoracic nodes

- Recurrence
      -He receives palliative therapy with oral procarbazine, etoposide, prednisone
      and cytoxan (PEPC) for 5 months until progression
      -He starts brentuximab vedotin and has disease controlled for several more
      months

Hodgkin’s Lymphoma
     -Epidemiology
            -Median age at presentation ~ 38
            -Median age of death from HL = 61
                  -This is a disease that is curable in young adults and worse
                  prognosis the older you get

                              Younger                   Older
Incidence                      Lower                    Higher
Mortalitiy                     HIGHER                   Lower


Non Hodgkin’s Lymphoma
       -Varied cells of origin – NO RS Cells
              -Predominantly B cells
              -T cell origin in small%
              -Divided into:
                      -Low grade
                      -Intermediate grade
                      -High grade
NHL – Types- don’t memorize! Follicular is Best Prog. B Cell is worse Prog.




NHL - Epidemiology
      -66,000 new cases this year
      -19,000 deaths due to NHL
      -Incidence is increasing – felt due to better detection and aging population
      -Deaths are decreasing from aggressive lymphomas
      -Indolent lymphoma death rates are staying stable

NHL - Presentation
      -Presents often in “non-contiguous” nodes –Hodgkin’s is contiguous
      -B symptoms may be present
      -Work up is similar to HL
      -Staging is identical


Case 3 – Initial Presentation
       -81 year old woman falls at home and presents to ER
       -Med history significant for rheumatoid arthritis
       -She takes methotrexate weekly
       -Mild functional limitations due to RA
       -Widowed but independent

Case 3 - Presentation
       -Fall is felt due to “weakness”
       -No hip pain or decreased consciousness
       -40 lb. weight loss due to anorexia and early satiety over 3-4 mos.
       -She has nightsweats for last month

Case 3- Exam
       -On exam she weighs 96 lbs and appears frail
       -She has dry mucous membranes
       -3 cm firm, left supraclavicular lymph node is palpated
       -Large, mid-line abdominal mass is palpated >10cm
       -Bilateral, pitting lower extremity edema

Case 3 – Work Up
       -CT scan confirms exam findings
       -Large intraperitoneal mass is shifting organs, compressing stomach
       -Innumerable lymph nodes are visualized above and below diaphragm

Case 3 - Diagnostics
       -Needle core biopsy of the mass shows diffuse large b cell lymphoma
       -Bone marrow biopsy shows involvement
       -CBC shows moderate anemia with hemoglobin of 9
       -Chemistries show slight elevation of BUN and creatinine
       -LDH is elevated – poor prognosis!




Case 3 - Prognostic Factors
*TQ* -The “IPI” is a score card of clinical characterisitics deemed favorable or
     unfavorable
            Factors
                     -Age > 60
                     -Serum LDH elevated
                     -ECog Performance Score >2 (higher is worse!)
                     -Ann Arbor III or IV
                     -# of extranodal disease sites >1
     -Higher scores convey worse prognosis
      -Elderly adults with higher stage disease fair worse

Case 3 - Treatment
      -Cyclophosphamide, Adriamycin, Vincristine and Prednisone (the
      aforementioned are like CLUSTERBOMSBS – destroy target and everything
      else) with Rituximab (smart missle!) (R-CHOP) is given
      -Six cycles is planned
      -She falls and fractures her hip after 4 cycles
      -She moves into a nursing home

Case 3 – Follow up
      -She stops chemotherapy early after a partial response
      -She regains weight and strength after several months
      -Moves back home with aid services
      -Disease remains stable but she eventually dies from heart failure

Lymphoma in Older Pts: Specific Issues
     -Role of comorbidity
     -Decreased complete response rate
     -Decreased survival
     -Increased risk of toxic death
     -Increased risk of death from non-lymphoma




                                                                           Elderly can’t
                                                                           handle the full
                                                                           dose  lower
                                                                           cure rate!




Case 4: Initial Presentation
      -67 yo woman presents with “knots” in her neck
      -They grew gradually over several months
         -History of waxing-waning “knots”
         -She has a history of thyroiditis
         -She feels well without B symptoms

Case 4 - Presentation
         -On exam she has painless, palpable supraclavicular and axillary
         lymphadenopathy
         -Goiter is present
         -Spleen is not palpable
         -No other nodes are palpable

Case 4 - Diagnostics
         -CBC and chemistries are normal
         -LDH is normal
         -CT scan of the body shows enlarged nodes in the chest, abdomen and pelvis
         – not impinging an organ

Case 4 – Work Up
         -Lymph node biopsy is performed
         -Pathology is consistent with follicular lymphoma, grade is 1 (of 3)

Case 4 - Treatment
         -The patient feels otherwise well and opts to be watched
         -She is followed for several months until she begins having pain associated
         with an axillary node
         -She begins treatment with rituximab (anti-CD20 antibody)
         -She achieves a complete remission for 3 years
         -She then receives radio-labeled antibody and achieves complete remission
         again
         -She has no side effects from therapy thus far


Follicular Lymphoma

-Grade 1, 2 indolent
      -Can be followed w/o treatment for months to years
      -Spontaneous remission possible
      -Generally, not curable

-Grade 3 – aggressive
      -Require treatment similar to diffuse large B cell lymphoma
      -Can be cured with chemotherapy


Case 5
         -54 yo female horse trainer develops progressive back pain
         -She is otherwise healthy, never smoked
      -Recent mammogram normal
      -Family history is negative
      -ROS is significant for fatigue, excessive thirst and urination

Case 5 - Exam
      -She appears in distress due to pain
      -Dry mucous membranes
      -Heart and lungs normal
      -Point tenderness over lower thoracic spine
      -Decreased lower extremity reflexes

Case 5 – Work Up
      -CBC
            -WBC = 11.2
            -Hgb = 9.3
            -Plt = 233,000
      -Chemistry significant for
            -Creatinine = 2.3 (normal 0.8-1.2) measure renal fnx
            -Calcium = 13.7 (normal 8-10)
            -Albumin = 2.6 (normal 3.5-4)
            -Total protein = 12 (normal 7)     increased immunoglobulin

Case 5 – Work Up
      -T11 lytic lesion
      -Spinal cord being displaced
      -What is going on with this patient?
      -What further studies should be done?
      -What should be done for her hypercalcemia?
      -What should be done for her impending neurologic condition?

Case 5 - Differential Diagnosis
      -Patient has back pain caused by a lytic lesion, hypercalcemia, renal failure
      and anemia
             -Think cancer (lung, breast, myeloma)
             -Other causes of hypercalcemia
                    -PTH adenoma,Vitamin D overdose, Sarcoidosis
             -Other causes of lytic lesions
                    -Primary bone tumors/sarcomas

Case 5 – Work Up
      -Serum Protein Electropheresis (SPEP)
      -M protein – “spike” implies “monoclonal” protein
      -M protein can be IgG, IgA, IgM, IgD
      -Free light chains found in serum, missed by SPEP
      -Implicated in renal tubule destruction
      -Assay for serum free light chains useful to diagnose and monitor disease
      -Patient has M-protein of 4.5 g/dl which is lamda and IgG
      -Free light chains are 11,000
      -Quantitative immunoglobulins show high IgG of 5000, low IgA and IgM
      fractions
      -Beta 2 microglobulin is very high at 8
      -ESR is 85
      -Bone marrow biopsy shows sheets of plasma cells


Myeloma – Bone Marrow
      -> 30% plasma cells indicative of myeloma
      -10-20% and no other signs  smoldering myeloma
      -<10%  monoclonal gammopathy of unknown significance


Case 5 - Treatment
      -Patient is started on high dose steroids (dexamethasone)
      -Radiation Oncology and Neurosurgery are consulted
      -She receives radiotherapy to her spine
      -Pain and neurologic function improve

Myeloma – Treatment
     -Epidural Cord Compression
           -Most serious complication of bone lesions
           -Paralysis can result if diagnosis and treatment delayed
                  -MRI emergently to evaluates suspicous symptoms
                  -High dose steroids immediately
           -Radiation vs. neurosurgical decompression emergently if diagnosed


********Case 5 – Treatment Hypercalcemia*********
      -IV normal saline and lasix improves calcium
      -Renal function improves
      -IV pamidronate given
      -Calcium returns to normal
      -Lethargy reverts

Myeloma – Bone Dz
     -Myeloma cells produced PTH-rp
     -Induces bone  activates osteoclasts
     -Cytokines released by osteoclasts feedback to induce growth of myeloma
     cells
     -Vicious cycle that can be broken by IV bisphosphonates
Case 5 - Treatment
         -Patient stabilizes with normal renal function and calcium
         -Pain and neurologic status normalize
         -She begins pulsed dexamethasone with thalidomide

Treatment - Thalidomide
      -Thalidomide interferes with angiogenesis
      -Immune modulator in the bone marrow to stimulate apoptosis
      -Synergistic with dexamethasone
      -Causes sedation, constipation, neuropathy and blood clots
      -Does not damage stem cells

Myeloma - Treatment
     -Patient responds after 4 mos. w/ undetectable M-protein
     -Stem cells harvested
     -Autologous stem cell tranplant
     -Complete remission attained lasting 4 years
     -After 1st Transplant
             -Patients can have second ASCT
             -Maintenance drugs used frequently after ASCT
             -Consider allogeneic transplant if good match
             -Salvage regimens include
                    -Lenolidaminde
                    -Bortezomib
                    -Liposomal doxorubicin

Case 6
         -68 yo woman with chronic back pain, osteoporosis
         -Back pain worsens last few weeks
         -Tylenol and NSAIDS do not help
         -No fevers or neurologic changes

Case 6 - Exam
         -She is tender over the lumbar spine
         -Normal reflexes and sensation in lower extremities
         -Gait is normal

Case 6 – Work Up
         -CBC and differential is normal
         -Metabolic panel is normal
         -Total protein is normal

Case 6 – Diff Dx
         -What are the possible benign causes of this woman’s presentation?
         -What further studies should be done?
Case 6 – Work Up
       -L2 compression fracture seen on plain films AP and lateral
       -MRI – pre-kyphoplasty showed a mass around L2
       -Bone biopsy was done during kyphoplasty
       -Sheets of kappa restricted plasma cells were seen
       -Pain was relieved after kyphoplasty
       -Skeletal survey was negative (other than the compression fx)
               -No lytic lesions seen
       -SPEP and Free light chains were negative
       -Bone marrow biopsy from posterior, superior iliac crest showed no plasma
       cell clones

Solitary Plasmacytoma
       -Cell of origin related to multiple myeloma (plasma cell)
       -Can be in any bone or extra-medullary (soft tissue)
       -Respond well to RT alone
       -Associated with progression to overt multiple myeloma

Case 6 - Treatment
       -Patient received involved field RT
       -She is pain free and functional afterwards
       -Follow up SPEP and free light chains remain negative after several years
       -CBC and renal function are normal on continued follow up


MULTIPLE MYELOMA
     C – calcium is high
     R - renal
     A - anemia
     B - bone


Lecture 10/11 Lymphadenopathy
Overview of Lymphatic System
      •The lymphatic system is a subsystem of the circulatory system.
      •Its three principal functions are: **TQ**
             1.) to collect and return interstitial fluid, including plasma
                     protein to the blood, and thus help maintain fluid balance,
             2.) to defend the body against disease by producing lymphocytes,
             3.) to absorb lipids from the intestine and transport them to the
                     blood.

Various conditions can cause chylothorax.
      – Mediastinal tumors are the most common cause, lymphomas > metastatic
       –Chylothorax frequently complication rare disease lymphangiomyomatosis.
       – Triglyceride > 110 mg/dl;
              - exceptions usually are limited to patients in whom feedings have
              been withheld, such as post-op pts.
       –The major consequence of chylous effusions is the rapid and recurrent
       accumulation of liquid in the pleural space.
              –Normally, the thoracic duct transports chyle at a rate of 1.5 to 2.5
              L/day. In patients with chylothorax, much or all of this liquid may
              enter the pleural space.

The Thoracic Duct
      • conveys the great mass of lymph and chyle into the blood.
      •It is the common trunk of the lymphatic vessels of the body,
               -Except: R side of head, neck, thorax, lung, heart and upper extremity
               and the convex surface of the liver.
      •The thoracic duct lies on the posterior thoracic and abdominal wall between
      the aorta and azygous vein - extends from the 2nd lumbar vertebra to the
      root of the neck.

Anatomy- skimmed
     •The lymphatic system consists of a network of vessels that drain tissue fluid
     (lymph) into lymph nodes, larger fluid-containing lymph ducts, and
     specialized organs involved in the immune system.
     •The lymph nodes and organs act as a type of “filter,” removing invading
     organisms or abnormal cells from the lymph fluid and “processing” them in a
     way that allows the body to fight these harmful agents.
     •The bean-shaped lymph nodes of the lymphatic system are connected by
     vessels.
     •Lymph nodes are usually present in clusters in the armpits, on either side of
     the neck, and in the groin.
     •The lymph nodes filter lymph fluid and trap foreign materials.
     •Any fluid absorbed by the lymphatic system passes through at least one
     lymph node before it returns to circulation.

Diagnostic Approach to Lymphadenopathy
      -The algorithm emphasizes that a careful history and physical examination
      are the core of the evaluation. In most cases, a careful history and physical
      examination will identify a readily diagnosable cause of the
      lymphadenopathy, such as
             –upper respiratory tract infection
             –Pharyngitis
             –periodontal disease
             –Conjunctivitis
             –Lymphadenitis
             –Tinea
             –insect bites
             –recent immunization
             –cat-scratch disease or dermatitis
      and no further assessment is necessary (see the "diagnostic" branch of the
      algorithm).

      -In other cases, a definitive diagnosis cannot be made on the basis of the
      history and physical examination alone; however, the clinical evaluation may
      strongly suggest a particular cause.
      -Confirmatory testing should be performed in order to correctly identify the
      patient's illness (see the "suggestive" branch of the algorithm).




Physical Examination
      -When lymphadenopathy is localized, the clinician should examine the region
      drained by the nodes for evidence of infection, skin lesions or tumors.
      -Other nodal sites should also be carefully examined to exclude the
      possibility of generalized rather than localized lymphadenopathy.
             -This is an important aspect of the examination, as a study of primary
             care physicians found that generalized lymphadenopathy was
             identified in only 17 percent of the pts in whom it was present.
      -Careful palpation of the submandibular, anterior and posterior cervical,
      supraclavicular, axillary and inguinal nodes can be accomplished in a short
      time and will identify patients with generalized lymphadenopathy.
Fine-needle aspiration is occasionally considered an alternative to excisional
biopsy but is often unhelpful.
       –Size. Nodes are generally considered to be normal if they are up to 1 cm in
       diameter; however, some authors suggest that epitrochlear nodes larger than
       0.5 cm or inguinal nodes larger than 1.5 cm should be considered
       abnormal.7,8
       –Little information exists to suggest that a specific diagnosis can be based on
       node size. However, in one series10 of 213 adults with unexplained
       lymphadenopathy, no patient with a lymph node smaller than 1 cm2 (1 cm 3
       1 cm) had cancer, while cancer was present in 8 percent of those with nodes
       from 1 cm2 to 2.25 cm2 (1 cm 3 1 cm to 1.5 cm 3 1.5 cm) in size, and in 38
       percent of those with nodes larger than 2.25 cm2 (1.5 cm 3 1.5 cm).
       –In children, lymph nodes larger than 2 cm in diameter (along with an
       abnormal chest radiograph and the absence of ear, nose and throat
       symptoms) were predictive of granulomatous diseases (i.e., tuberculosis, cat-
       scratch disease or sarcoidosis) or cancer (predominantly lymphomas).11
       These studies were performed in referral centers, and conclusions may not
       apply in primary care settings.

Pain/Tenderness. When a lymph node rapidly increases in size, its capsule
stretches and causes pain. Pain is usually the result of an inflammatory process or
suppuration, but pain may also result from hemorrhage into the necrotic center of a
malignant node. The presence or absence of tenderness does not reliably
differentiate benign from malignant nodes.4
 Consistency. Stony-hard nodes are typically a sign of cancer, usually metastatic.
Very firm, rubbery nodes suggest lymphoma. Softer nodes are the result of
infections or inflammatory conditions. Suppurant nodes may be fluctuant. The term
"shotty" refers to small nodes that feel like buckshot under the skin, as found in the
cervical nodes of children with viral illnesses.
 Matting. A group of nodes that feels connected and seems to move as a unit is
said to be "matted." Nodes that are matted can be either benign (e.g., tuberculosis,
sarcoidosis or lymphogranuloma venereum) or malignant (e.g., metastatic
carcinoma or lymphomas).
Location. The anatomic location of localized adenopathy will sometimes be helpful
in narrowing the differential diagnosis. For example, cat-scratch disease typically
causes cervical or axillary adenopathy, infectious mononucleosis causes cervical
adenopathy and a number of sexually transmitted diseases are associated with
inguinal adenopathy

Supraclavicular lymphadenopathy
      -has the highest risk of malignancy, estimated as 90 percent in patients older
      than 40 years and 25 percent in those younger than age 40.4 Having the
      patient perform a Valsalva's maneuver during palpation of the
      supraclavicular fossae increases the chance of detecting a node.
       •Lymphadenopathy of the right supraclavicular node is associated with
       cancer in the mediastinum, lungs or esophagus.
       •The left supraclavicular (Virchow's) node receives lymphatic flow from the
       thorax and abdomen, and may signal pathology in the testes, ovaries,
       kidneys, pancreas, prostate, stomach or gallbladder. Although rarely present,
       a paraumbilical (Sister Joseph's) node may be a sign of an abdominal or
       pelvic neoplasm.12
       •In patients with generalized lymphadenopathy, the physical examination
       should focus on searching for signs of systemic illness. The most helpful
       findings are rash, mucous membrane lesions, hepatomegaly, splenomegaly or
       arthritis (Table 4). Splenomegaly and lymphadenopathy occur concurrently
       in many conditions, including mononucleosis-type syndromes, lymphocytic
       leukemia, lymphoma and sarcoidosis.

•Clinical Case
Cat-Scratch Disease
                                 -Cat-scratch disease is a common, benign condition, most
                                 often caused by Bartonella henselae.
                                        -It is transmitted by a bite or scratch of a kitten or a
                                        cat with fleas or occasionally, that of an other pet.
                                        -Peak transmission is in the early fall or winter. The
                                        condition characteristically affects children and
                                        adults younger than 21 years.
                                        -The vast majority of patients can recall a history of
                                        cat contact, but not all. Typically, within 2 to 3 days
                                        of inoculation, a papule develops and progresses to a
                                        vesicle, which is followed by proximal
                                        lymphadenopathy in about two weeks. In fewer than
                                        6% of patients, the primary lesion is followed by a
                                        generalized macular-papular and morbilliform
                                        eruption.
                                        -The involved lymph nodes are tender, often with
                                        overlying erythema; occasionally they can
                                        suppurate.
                                        -The lymphadenopathy subsides spontaneously after
                                        several months. The diagnosis of cat-scratch disease
                                        is primarily clinical.


Spread of Disease
      •The materials most commonly spread via the lymph vessels from their
      original site to the circulating blood are fragments of tumours and infected
      material.
–Fragments of tumours :
      •Tumor cells may enter a lymph capillary draining a tumour, or a larger
      vessel when a tumour has eroded its wall. Cells from a malignant tumour, if
       not phagocytosed (eaten by white blood cells), settle and multiply in the first
       lymph node they encounter.
       • Later there may be further spread to other lymph nodes, to the blood and to
       other parts of the body via the blood.
       •In this sequence of events, each new metastatic tumour becomes a source of
       malignant cells that may spread by the same routes.
–Infected material : Infected material may enter lymph vessels either at their origin
       in the interstitial spaces, or through the walls of larger vessels invaded by
       microbes when infection spreads locally . If phagocytosis is not effective the
       infection may spread from node to node, and eventually reach the blood
       stream.

Lymphadenopathy
     -Review the lymphatic system and its pathology
           -Enlargement of nodes
           -Correlate with appropriate lymphatic regions

Sites of Lymphadenopathy
       -Lymph nodes are found throughout the body the picture shows the
       positioning of some of the major groups of lymph nodes.
              [1] Mastoid and Sub occipital nodes of the head
              [2] Cervical lymph nodes of the neck
              [3] Axillary lymph nodes under the arms
              [4] Inguinal lymph nodes of the groin area
              [5] Popliteal noded behind the knee
       -An enlargement of these nodes is common in
       inflammation and malignant disease. As a result
       palpation (feeling) of the neck, armpits and the groin
       area is an important part of clinical investigation

Medications that cause adenopathy
     Allopurinol (Zyloprim)          Atenolol (Tenormin)
     Captopril (Capoten)             Carbamazepine
                               (Tegretol)
     Cephalosporins                  Gold
     Hydralazine (Apresoline)        Penicillin
     Phenytoin (Dilantin)            Primidone (Mysoline)
     Pyrimethamine (Daraprim)         Quinidine
     Sulfonamides                     Sulindac (Clinoril)


The lymphatic system
      -is a network of lymph nodes connected by lymphatic vessels.
              – Lymph nodes contain a mesh of tissue in which lymphocytes are
              tightly packed. This mesh of lymphocytes filters, attacks, and destroys
              harmful organisms that cause infections.
      – Lymph nodes are often clustered in areas where the lymphatic
      vessels branch off, such as the neck, armpits, and groin.
      -Lymph, a fluid rich in white blood cells, flows through the lymphatic vessels.
      Lymph helps return water, proteins, and other substances from the body's
      tissues to the bloodstream. All substances absorbed by the lymph pass
      through at least one lymph node and its filtering mesh of lymphocytes.
      -Other bodily organs and tissues--the thymus, liver, spleen, appendix, bone
      marrow, and small collections of lymphatic tissue such as the tonsils in the
      throat and Peyer's patch in the small intestine--are also part of the lymphatic
      system. They too help the body fight infection

Lymphadenopathy
     •Inflammatory pseudotumor of lymph node
Case
                                                          Diagnosis

                                                          Lymphagitis




Lymphangitis
     •Lymphangitis (infection of lymph vessel walls) : This occurs in some acute
     pyogenic infections in which the microbes in the lymph draining from the
     area infect and spread along the walls of lymph vessels, e.g. in acute
     Streptococcus pyogenes infection of the hand, a red line may be seen
     extending from the hand to the axilla.
     •This is caused by an inflamed superficial lymph vessel and adjacent tissues.
     The infection may he stopped at the first lymph node or spread through the
     lymph drainage network to the blood.

Clinical Assessment

      ►The physician will be aided in the pursuit of an explanation for the
      lymphadenopathy by a careful medical history, physical examination,
      selected laboratory tests, and perhaps an excisional lymph node biopsy.
      ►The medical history should reveal the setting in which lymphadenopathy is
      occurring.
             ►Symptoms such as sore throat, cough, fever, night sweats, fatigue,
             weight loss, or pain in the nodes should be sought.
             ►The patient's age, sex, occupation, exposure to pets, sexual
             behavior, and use of drugs such as diphenylhydantoin are other
             important historic points.
                   ► For example, children and young adults usually have benign
                   (i.e., nonmalignant) disorders, such as viral or bacterial upper
                   respiratory infections.
                   ►The size and texture of the lymph node(s) and the presence
                   of pain are useful parameters in evaluating a patient with
                   lymphadenopathy. Nodes <1.0 cm2 in area (1.0 × 1.0 cm or
                   less) are almost always secondary to benign, nonspecific
                   reactive causes Nodes>2.5 cm2 have a increased incidence of
                   malignancy or atypical infection.
                   ►In contrast, after age 50 the incidence of malignant disorders
                   increases and that of benign disorders decreases.


Diagnosis


      • Approach to the Patient
      •Lymphadenopathy may be a primary or secondary manifestation of
      numerous disorders, as shown in Table 63-1.
      •Many of these disorders are infrequent causes of lymphadenopathy.
      •Analysis of lymphadenopathy in primary care practice has shown that:
             – more than two-thirds of patients have nonspecific causes or upper
             respiratory illnesses (viral or bacterial)
             – fewer than 1% have a malignancy.
      •In one study, researchers reported that 186 of 220 patients
             –(84%) referred for evaluation of lymphadenopathy had a "benign"
             diagnosis.
                     •Sixty-three percent (112) of the 186 patients with benign
                     lymphadenopathy had a nonspecific or reactive etiology (no
                     causative agent found)
                     •remainder had a specific cause demonstrated, most
                     commonly infectious mononucleosis, toxoplasmosis, or
                     tuberculosis
             –The remaining 34 patients (16%) had a malignancy (lymphoma or
             metastatic adenocarcinoma).
      •Thus, the vast majority of patients with lymphadenopathy will have a
      nonspecific etiology requiring few diagnostic tests.

Diagnosis
      •The site of localized or regional adenopathy may provide a useful clue about
      the cause.
      • Occipital adenopathy often reflects an infection of the scalp
      • preauricular adenopathy accompanies conjunctival infections and cat-
      scratch disease.
      •The most frequent site of regional adenopathy is the neck, and most of the
      causes are benign-upper respiratory infections, oral and dental lesions,
      infectious mononucleosis, other viral illnesses.
      •The chief malignant causes include metastatic cancer from head and neck,
      breast, lung, and thyroid primaries.
      •Enlargement of supraclavicular and scalene nodes is always abnormal.
      Because these nodes drain regions of the lung and retroperitoneal space,
      they can reflect either lymphomas, other cancers, or infectious processes
      arising in these areas. Virchow's node is an enlarged left supraclavicular
      node infiltrated with metastatic cancer from a gastrointestinal primary.).
      -Metastases to supraclavicular nodes also occur from lung, breast, testis, or
      ovarian cancers. Tuberculosis, sarcoidosis, and toxoplasmosis are
      nonneoplastic causes of supraclavicular adenopathy.
      -Axillary adenopathy is usually due to injuries or localized infections of the
      ipsilateral upper extremity. Malignant causes include melanoma or
      lymphoma and, in women, breast cancer.
      -Inguinal lymphadenopathy
              – Secondary to infections or trauma of the lower extremities and
               may accompany sexually transmitted diseases such as
              lymphogranuloma venereum, primary syphilis, genital herpes, or
              chancroid.
              –These nodes may also be involved by lymphomas and metastatic
              cancer from primary lesions of the rectum, genitalia, or lower
              extremities (melanoma)
      •The physical examination can provide useful clues such as the extent of
      lymphadenopathy (localized or generalized), size of nodes, texture, presence
      or absence of nodal tenderness, signs of inflammation over the node, skin
      lesions, and splenomegaly.
      •A thorough ear, nose, and throat (ENT) examination is indicated in adult
      patients with cervical adenopathy and a history of tobacco use. Localized or
      regional adenopathy implies involvement of a single anatomic area.
      •The size and texture of the lymph node(s) and the presence of pain are
      useful parameters in evaluating a patient with lymphadenopathy. Nodes
      <1.0 cm2 in area (1.0 × 1.0 cm or less) are almost always secondary to
      benign, nonspecific reactive causes
      •Generalized adenopathy has been defined as “involvement of three or
      more noncontiguous lymph node areas”.
      •Acute and chronic lymphocytic leukemias and malignant lymphomas also
      produce generalized adenopathy in adults.

Laboratory studies
      •Laboratory Investigation
•The laboratory investigation of patients with lymphadenopathy must
be tailored to elucidate the etiology suspected from the patient's
history and physical findings. One study from a family practice clinic
evaluated 249 younger patients with "enlarged lymph nodes, not infected" or
"lymphadenitis." No laboratory studies were obtained in 51%. When studies
were performed, the most common were a complete blood count (33%),
throat culture (16%), chest x-ray (12%), or monospot test (10%).
•Only eight patients (3%) had a node biopsy, and half of those were normal
or reactive.
•The complete blood count can provide useful data for the diagnosis of
acute or chronic leukemias, EBV or CMV mononucleosis, lymphoma with a
leukemic component, pyogenic infections, or immune cytopenias in illnesses
such as SLE.
•The chest x-ray is usually negative, but the presence of a pulmonary
infiltrate or mediastinal lymphadenopathy would suggest tuberculosis,
histoplasmosis, sarcoidosis, lymphoma, primary lung cancer, or metastatic
cancer and demands further investigation.
•A variety of imaging techniques [computed tomography (CT), magnetic
resonance imaging (MRI), ultrasound, color Doppler ultrasonography] have
been employed to differentiate benign from malignant lymph nodes,
especially in patients with head and neck cancer. CT and MRI are comparably
accurate (65 to 90%) in the diagnosis of metastases to cervical lymph nodes.
Ultrasonography has been used to determine the long (L) axis, short (S)
axis, and a ratio of long to short axis in cervical nodes. An L/S ratio of
<2.0 has a sensitivity and a specificity of 95% for distinguishing benign
and malignant nodes in patients with head and neck cancer. This ratio
has greater specificity and sensitivity than palpation or measurement of
either the long or the short axis alone.
•Most lymphadenopathy patients do not require a biopsy, and at least half
require no laboratory studies.
•If the patient's history and physical findings point to a benign cause for
lymphadenopathy, then careful follow-up at a 2 to 4 week interval can be
employed. The patient should be instructed to return for reevaluation if the
node(s) increase in size.
•Antibiotics are not indicated for lymphadenopathy unless there is strong
evidence of a bacterial infection.
•Glucocorticoids should not be used to treat lymphadenopathy because their
lympholytic effect obscures some diagnoses (lymphoma, leukemia,
Castleman's disease) and they contribute to delayed healing or activation of
underlying infections.
•An exception to this statement is the life-threatening pharyngeal
obstruction by enlarged lymphoid tissue in Waldeyer's ring that is
occasionally seen in infectious mononucleosis.
•Summary: Since most cases of lymphadenopathy are nonspecific the most
prudent form of treatment is to follow clinically and wait for resolution
Treatment
      -Most cases of adenopathy are nonspecific and do not require specific
      treatment , but need to be followed until resolution.
      -Infectious causes should treated appropriately with antibiotics /antifungals
      or nodal resection.
      -Malignant adenopathy usually require biopsy and specific treatment.

Lymphedema
     What is Lymphedema?
          -Lymphedema can be defined as an accumulation of excessive
          proteins, edema, chronic inflammation, and fibrosis secondary to the
          impairment of the lymph vessels. The vessels transport molecules to
          the venous angle of the neck where the lymph system joins the venous
          system.
     Are there different kinds of Lymphedema?
          -Yes. Lymphedema can be either primary or secondary lymphedema.

             –Primary lymphedema is usually due to either a congenital
             absence of, or abnormalities in, lymphatic tissue. It can be
             hereditary (Milroy Disease), lymphedema praecox (onset during
             puberty), or lymphedema tarda (onset later in life). Primary
             lymphedema is more prevalent in females than males.

             –Secondary lymphedema is generally caused by an obstruction or
             interruption of the lymphatic system, usually caused by malignancies,
             infection, trauma, excision, or post-radiation fibrosis.

      Incidence
           -It is not known the true number of persons suffering from
           lymphedema. It is estimated that the incidences of lymphedema in the
           United States are as follows :
                    –Primary Lymphedemia:1-2 million
                    –Secondary Lymphedemia: 2-3 million


Lymphedema : Causes of Lymphedema
– Primary Congenital
      -Milroy's disease
      -Lymphedema praecox          (includes Meige’s disease)
      -Lymphedema tarda
–Secondary
      -Recurrent lymphangitis (Filariasis)
      -Tuberculosis
      -Neoplasm
       -Surgery
       -Radiation therapy

Lymphedema: Introduction to the lymphatic system

Treatment for Lymphedema
•Lymphedema can be managed so that you can resume your normal lifestyle. Each
case varies. A physical therapist will work with you to help develop a customized
program that best suits your needs. The following techniques are used to treat
lymphedema. We may use all or any combination of them to treat your condition.

Exercise
•You will be given a series of exercises that will strengthen the muscles that have
been affected and help you regain any flexibility you may have lost. Aerobic exercise
will be included to help increase the lymph flow back to your heart. Exercises for
flexibility and strengthening will help you regain full function. Strengthening and
aerobic exercise, combined with bandaging, can help reduce the swelling.

Bandaging
•You will be taught to wrap your arm with special bandages at your first or second
treatment. A type of bandage called a compression bandage is best suited for
lymphedema because it applies a low amount of pressure that does not cut off
circulation. This special compression bandage looks like an ace wrap but applies
different pressures when your muscles are at rest and at work. The combination of
muscle contraction and bandaging pumps the fluid out of your arm. Once the
swelling has stabilized, you may be fitted with a custom garment or sleeve,
depending on your particular needs for work and daily activities.
•Treatment continued

Manual lymph therapy
•Manual lymph therapy is a light, circular massage starting at the neck and working
down the affected area. It uses alternating pressures to improve absorption of
lymph fluid. The fluid-filled tissue is softened through changes in tissue pressure.
Excess protein is moved out of the limb, and fluid follows the protein molecules.
•With manual lymph therapy, we push lymph fluid away from damaged or blocked
lymph nodes to healthy pathways. Again, these may vary from patient to patient.
With treatment, the body may even develop additional lymph pathways to handle
the increased volume of lymph fluid in a particular area.

Compression pumps
•Pumps are sometimes used in treatment of lymphedema. Once you have learned
how to use the pump, you may be given a home unit. The pump helps the veins carry
more fluid back to the heart
Lecture 12, 13 and 14: The Chronic Leukemias (myeloid and
lymphoid), Myeloproliferative Neoplasms, Myelodysplastic
Syndromes, The Acute Leukemias (myeloid and lymphoid)

Three Hours of Torture: A Summary
      -Hematopoiesis and CBC basics
      -A primer on bone marrow interpretation
      -When good cells go bad
      -Lots of minute details
      -Laboratory analysis
      -Current therapeutics
      -The genome is the wave of the future

Myeloblast
      -A very early cell
      -Often difficult to tell myeloid from lymphoid
    -Look for an Auer Rod
          - There are 1 to 5% in the marrow aspirate and should be ‘none’ in the
          peripheral blood

     Promyelocyte - DIC
           -lots and lots of primary granules
           -When the leukemic cell line, coagulation problems will occur
           -Trans-retinoic acid can turn this into a myelocyte!

     Myelocyte
            -Not the absence of primary granules
            - The ‘dawn of neutrophilia”

     Metamyelocyte
         -Let the indentation begin

          Neutrophil- Grunt Warrior
              -Too many names
              -Polymorphonuclear Cell – PMN
              -Granulocyte
              -Neutrophil
              -Segmented cell

          Eosinophil

     Basophil - Rare Bear
Infectious Mononucleosis
     -Large, busy monocytes with deep blue cytoplasm, nucleoli and they seem
     to hug their blood cells

Proper blood smears and microscopes
    -Not too short
    -Not too long
    -Feathered edge
    -Zone of holes
    -Zone of morphology
    -Zone of clumping

The Complete Blood Count
     -Hct/Hgb 45/15 (5 million red cells – Retic is 1% of this)
     -Platelets 150 to 400K
     -White Cells      5-10K
                -Polys       60%
                -Lymphs      30%
                -Monos       8%
                -Eos         1.5%
                -Basos       0.5%

Question 1:
    -A pt presents to your office for routine follow up and labs after being
    seen in urgent care for bronchitis. He was given an antibiotic and feels
    better. His WBX is 5000 and total lymphs are 70%? Total neutrophils/
    granulocutes are 30$ of the differential. The absolute lymphocyte cout is:
       A. 7,000
       B. 10,000
       C. 3, 500

Bonus Question
    -What is the patient’s absolute neutrophil count?
       A. 5000
       B. 10,000
       C. 15,000
       D. 1,500

     Topic One: MYELOPROLIFERATIVE NEOPLASMS MPN
          -Used to be called the myeloproliferative disorders, MPDs and there
          were only four
          -These are all caused by mutated genes that allow uninterrupted
          cellular proliferation
          -“Effective” hematopoiesis is the rule
             -normal cells just TOO much!
         -There are still only four that dominate, with the others something I
         may see once.

    1.) CML
    2.) Polycythema Vera
    3.)Essential Thrombocytosis
    4.) Primary Marrow Fibrosis – Myeloid Metaplasia w/ Myelofibrosis

1.) Chronic Myelogenous Leukemia
    -15-20% of all adult leukemias
    -1 to 2 per 100,000 annual incidence
    -Slight male predominance
    -Peak age b/t 50 and 60 years
    -Only know risk factor is exposure to ionizing radiation
    -Signs and Symptoms
        -Fatigure weight loss, night sweats, pruritis, abdominal pain and
        fullness
        -Leukocytosis:         ~100%
        -Splenomegaly:         ~50-75%
        -Thrombocytosis: 25 to 50%
        -Hepatomegaly:         25%
    -Differential Diagnosis
        -CMML or chronic myelomonocytic leukemia (a form of
        myelodysplastic syndrome with lots of monocytoid cells)
        -Leukemoid Reactions: lots of ICU hematology consults
        -Polycythemia vera
    -Peripheral Blood Smear                           Test Question – CML
               -Lots of WBCs                          you see a lot of
               -Lots of early forms                   everything EXCEPT
               -Lots of platelets                     Blast.
               -Lots of Red Cells                     Lots of Blast in AML!
               -Lots of basophils
    **TQ** -NOT A LOT OF BLASTS
    -Other Lab Tests
               -Very low leukocyte alkaline phosphatase (LAP)
               -Ultrasound the left upper quadrant – for splenomegaly
               -BM or peripheral blood sample to find the 22:9 translocations
                      (cytogenetics)
               -PCR to find a very small clone of the Philadelphia
               Chromosome 9:22 BCR:ABL
    -Lab Analysis
               -When the bone marrow aspirate and the peripheral blood
               smear look amazingly alike – think CML
               -Cytogenetics is the ‘ancient’ art of cutting and pasting
                      -Requires a living marrow sample to grow in culture
                      -Labor intesive and expensive
              -In situ hybridization
                      -Able to detect the fusion of the DNA in the peripheral
                      blood or marrow aspirate
                      -Relatively easy and does not require a bone marrow
                      biopsy
              -Polymerase Chain Reaction
                      -PCR for short, can look at DNA or RNA
                      -Able to find infinitesimally small residual copies of
                      mutated genes
                      -Uses peripheral blood and also avoids BMBx
     -Treatment
              -Then
                      -“three to five” years of life then blast off to AML
                      -Hydroxyurea
                      -Busulfan
                      -Alpha interferon 1981, highest yet inducer of complete
                             remission including 2% of cytogenetic clearing
              -Now
                      -“Who knows?”
                      -Imatinib mesylate or STI 571 or Gleevec or Glivec in
                      Europe
                      -Allogenic Bone Marrow Transplantation
                      -Basatinib and Nilotinib, new TKIs

Tyrosine Kinases
    -90 human TK divided into two classes: receptor and non-receptor
    -MAbs can attack those on a membrane (receptor)
    -“Small molecules” bind the ATP sites on the others
    -All tyrosine kinases do the same thing – they transfer a phosphate group
    from ATP to ther respective kinase domain
        -Mission Possible: find the kinase and block phosphate transfer!

Imatinib (Gleevec)
        -Block the ABL tyrosine kinase (blackboard to bench to bedside)
        -5 years experience with the durg
        -Completely upsets the apple cart
        -In Chronic Phase (400-800mg/ day)
        -98% complete response clinically (CR)
        -86% complete response cytogentically (CCR)
        -?higher doses = better remission= longer life

NEJM: Gleevec vs. IfN/Ara-C
       -1100 pts randomized to either path, reported in 2003
       -CHR = complete hematologic response was 97% vs 69%
        -CCR = complete cytogenetic response was 76% vs. 14%
        -At 42 months DFS was 84% with Gleevec

With Gleevec: Accelerated Phase
        -CHR = complete hematologic response was 34%
        -CCR = complete cytogenic response was 24%
        -At two years, 50% had relapsing disease

Blast Phase
        -Blast are now exceeding 30% in the peripheral blood or marrow and
        may be myeloid (>60%) or lymphoid (30%)

Bone Marrow Transplantation
       -90 pts reported who underwent BMTx
       -Long follow-up
       -31.5% alive past 10 years
       -Median time to relapse was 7.7 years

New England Journal of Medicne Vol. 354, June , 2006
       -Nilotinib
              -a new TKI with higher affinity to BCR-ABL site
              -92% response rate in chronic phase previously resistant
              -74% response rate in accelerated phase
              -Very short in blast phase
              -Forget T315I
    -Dasatinib
              -a new TKI to a different site in ABL
              -92% response rate in chronic phase
              -Over 12 month median duration of response
              -Major cytogenic response were seen
              -Forget T315I

Much Ado About Nothing?
       -5,430 new CML cases per year
       -610 deaths per year as current failure rate with Gleevec is 4%
       annually
       -6000 oncologist in the USA
       -2.1 Billion gross sales of Gleevec in 2004
       -Sprycel (basatinib) and Tasigna (nilotinib) are approximately 50%
       more expensive than Gleevec.
       -Gleevec is 50K/year, the others 75K/year

Monitoring A CML Pt
       -Bone marrow cytogenetics – ouch
       -BCR-ABL FISH – expensive but p. blood
       -Quantitative PCR amplification – “Cheap” and p. blood
        -Q3 month while on Gleevec due a FISH until CCR, the Q 3 month PCR
        to show minimal disease burdenBM Biopsy to assess clonal evolution

2.) Polycythemia Vera
        -But first……
                -Erythrocytosis is NOT the same thing as polycythemia
                -Many wasted trips to the hematologist result from a failure to
                take a Hx and perform an exam
                -Try checking the hemoglobin twice

False Erythocytosis
        -Red Cell Mass is not elevated
        -Plasma volume is low
        -Many names: reactive-, spurious-, stress-, Gaisbock’s-, pseudo-
        erythrocytosis
        -Unforutnantely, the test required to rule-out or rule-in are numerous
        and necessary

     True Erythrocytosis: Secondary
              -Congenital causes are rare
              -Acquired elevations of the red cell mass include:
                     -Hypoxia (in general)
                     -High altitidue-chronic
                     -Inadequate ventilation
                     -Anabolic steroids
                     -Epo-secreting tumors
                     -Pulomary arterio-venous malformations
                     -TOBACCO!!

     True Erythrocytosis: Primary Polycythemia Vera
              -True clonal, myeloproliferative neoplasm characterized by an
              absolute increase in RBC mass
              -Median age of dx – 60 years
              -2 per 100,000 incidence per year
              -Slight male predominance
              -Galen proposed the primary tx


     P. Vera: The Symptoms and Signs
          -Fatigue
          -Sweating
          -Pruritis
          -Increased attacks of gout
          -Family is starting to make comments like “Have you been to the
          beach?”
          -Erythromelalgia: painful, burning hands and feet in the absense of
          know neuropathy or PVD
          -Thrombosis (any kind)
          -Plethora, excorations, splenomegaly, hepatomegaly

     Making the Dx is Tricky
              -True elevation of Red Cell mass - >36 ml/Kg in males, >32 in
              females
              -Absense of secondary causes: especially to show the absnese
              of significant hypoxia
              -Organomegaly
              -Depressed EPO levels – stinky kerosene causes EPO to go UP!
              -Elevations of leukocytes and platelets with high LAP (of
              course no       22:9T)

     Test you can order
               -ABGs
               -Carboxyhemoglobin as a measure of CO exposure
               -PFT’s
               -Sleep studies
               -Hemoglobin electrophoresis
               -CXR
               -Additional tests that hematologist may order: Erythropoietin
               level, pulmonary consultation, RBC mass (in nuclear medicine
               dept.), CT or ultrasound of abdomen/ pelvis


     A new gene marker
              -JAK 2 Mutations
              ->95% of P. vera pts express this mutation
              ->50% of essential thrombocytosis pts express this mutation
              ->50% of primary marrow fibrosis pt express this mutation


Therapy: Polycythemia Vera
       -Phlebotomy to keep the HCT under 45 in men, 42 in women
       -Hydroxyurea if platelts rise over a million if thrombosis risk is high,
       or in the elderly
       -81mg ASA (325 proved to be risky in these pts)
       -Anagrelide, allopurinol as indicated

Polycythemia Vera
        -25% present with a thrombotic event
        -With phlebotomy and control of the WBCs and platelets, expect > ten
        years survival
        -Spent phase leads to myelofibrosis, transformation to acute
        leukemia, secondary malignancies (15%) and complications such as
        thrombosis and infection/bleeding

  Test Question: ALL MPN can become fibrotic


3.) Essential Thrombocytosis
    -Differential diagnosis includes iron deficiency, sepsis and malignancies
    -Rule out CML, P. Vera and MMMF
    -Bone marrow shows both fibrosis and increases in megakaryocytes
    -Diagnostic criteria: >600,000 platelets in absence of other cause, no
    22:9 T, no iron deficiency, no organomegaly and the bone marrow does
    not show fibrosis >1/3
    -JAK 2 positivity (helpful)
        -Treatment
               -Hydroxyurea
                       -Old
                       -Sort of Cheap
                       -Well tolerated
                       -Once per day
                       -Fewer complications
                       -May cause secondary mutations
               -Anagrelide
                       -Newer
                       -Not cheap
                       -Well tolerated
                       -BID or TID
                       -Higher complications
                       -Does not cause mutations

4.) Myeloid Metaplasia with Myelofibrosis aka Primary Marrow Fibrosis
     PMF
       metaplasia- hematopoiesis goes to the spleen/liver
       -5% of the myeloproliferative neoplasms
       -Men and women in their 60s and 70s
       -Sxs vary by advancing state but include fatugue, bone pain and ‘Big
       spleen” syndrone
       -CBC shows anemia, tear drop cells, leukocytosis with early forms,
    abnormal and increased platelets and sometimes megakaryocyte
    fragments in the peripheral blood
       -The bone marrow is key to dx
       -Silver stain (reticulin) shows extensive fibrosis
       -Megakaryocytes are either the primary problem or the poor
       innocent bystander in a sea of fibrocytic insanity. PDGF from
       clonal Megs leads to stimulation of fibrocytes
         -Myeloid elements become vanishing species

Another new gene marker
       -The MPL mutation: MPL W515L/K is present in a minority of PMF
       and Essential Thrombocytosis and nails the dx when seen with other
       clinical findings on exam, peripheral smear and bone marrow core
       biopsy

PMF
      -Myeloid metaplsai or agnogenic metaplasia is metastasis or
      reversion of hematopoiesis to the spleen, liver, lymph nodes and
      even kidneys
         -In the absence of the blood: marrow barrier early forms occur in the
         periphery
         -Organomegaly is a hallmark – splenomegaly!!
         -The disease runs a course from one to 15 years
         -Death is due to complications of immunity, anemia, transfusion
         excess, hemorrhage or leukemic transformation
         -Tx doesn’t even get its own slide!
                 -Oral chemo agents, transfusions, splenectomy!
         -NOT TRUE ANYMORE – RUXOLITINIB!!!

American Society of Hematology, 2011
 -The COMFORT 1 and 2 Studies
 -JAK upregualtion is the problem
 -STAT (signal transducers and activators of transcription) gets turned on and
 a variety of genes start to work
 -Ruxolitinib blocks both pathways – see slides
 -The results were a first-ever breakthrough!

TOPIC TWO: CHRONIC LYMPHOID LEUKEMIAS- “Smarties”
 1.) Classic CLL
 2.) Prolymphocytic Leukemia
 3.) Hairy cell leukemia
 4.) Large granular Lymphocytosis
 5.) Adult T-Cell Leukemia/Lymphoma

The Mature B and T Neoplasms
       -Any phase of the mature B cells an go awry
       -From the antigen naïve, to germinal B’s, post-germinal B’s (memory
       cells) and plasma cells (forming all of part of immunoglobulin)
       -The number of kinds of T cells is amazing, and we will look at just
       two:
               ATL and LGL
       -No Hodgkin, Non-Hodgkin or T-cell lymphomas, nor myeloma, nor
         amyloidosis

B-Lymphocyte Biology
      -Proposed Neoplastic Equivalent




     A.           CLL/WDLL
     B-E.                Nodular NHL
     F.           Immunoblastic NHL
     G.           MM or Waldenstroms
     H.           Burkitt’s

1.) Classic CLL
         -The most common of all leukemias
         -2.7/100,000 incidence each year with male predominance 2:1
         -Most pts are over 60 years of age
         -Symptoms
                1.) None (25%)
                2.) B-Symptoms – fever, chills, weight loss of >10% in the
                previous 6 months in 10%
                3.) Fatigue
         -Signs
                1.) Lymphadenopathy (50-90%)
                2.) Splenomegaly (25-50%)
                3.) Hepatomegaly (10-25%)
         -Lab Studies
         **TQ**-Blood Smear shows lymphocytosis and smudge cells
                -Thershold values debated but around 10,000 lymphocytes
                absolute      number
            -Anemia and thromobocytopenia in some
            -Autoimmune destruction of red cells or platelets occur
            -Hypogammaglobulinemia as the disease progresses
            -BMBx optional
            -Flow cytometry is key
-Differential Diagnosis
            -Infections
                     1.) Infectious mononucleosis
                     2.) Pertussis
                     3.) Toxoplasmosis
                             -flow cytometry, age and the peripheral smear
                             should be keys
            -Malignancies
                     1.) The leukemic phase of the lymphomas, especially
                     SLL
                     2.) Other CLLs
-Flow Cytometry
            -While the classic CLL cell looks mature it is immature both
                     functionally and developmentally
            -98% are B cells
            -Surface immunoglobins are weakly displayed
            -T cell antigen CD5+
            -B Cell antigen CD 19, 20, 21 are +
            -Cytogenetics are finally emerging, especially 13 delection and
                     trisomy 12
            -Epigenetic factors may be the key for those with none
-Diagnosis
            -CLL Classic
            ->5 to 10 thousand lymphocytes in peripheral blood
            -30% lymphocytes in the bone marrow
            -Flow cytometry shows a monoclonal population of B cells
            -Extremely low surface immunoglobulins
            -CD 5 +
            -CD19, 20, 21 +
            -Lymphocytosis persists over times
-Staging and Tx Strategy
            -In a disease with life expenctancy raning from one to >20
            years determining stage might seem important
            -Rai and Binet developed strategies in the 60s and 70s that are
            still in use today
            -Unfortunantly, that means we haven’t come very far
            -Generally speaking it is best to do nothing and see what the pt
            is       going to do
    -Rai Clinical Staging
            -Low risk - >5,000/ml lymphocytosis in p. blood and marrow
            >30% lymphocytes
                    -Intermediate risk = same plus adenopathy (stage I) or same
                    plus splenomegaly (stage II)
                    -High Risk = same plus hgb <11g/dl (stage III) or same plus
                    PLT <100,000 (stage IV)

          Role of CD38, ZAP-7- and VH gene mutation status
                    -Recent understanding of these lymphocytes may lead to better
                    predictors of disease course and hence the need to tx early or
                    late
                    -For us aging oncologist, it will take a powerful study before a
                    simple test replaces staying the therapeutic hand, as we hold
                    the sweaty hand of a pt while we both watch and wait

          What if we actually do have to tx
                   -Worsening lymphocytosis usually around 100,000 cells
                   -Symptomatic anemia or thrombocytopenia
                   -Progressive disease burden: “B” symptoms, splenomegaly,
                          painful lymph nodes
                   -Autoimmune phenomena
                   -Hypogammaglobulinemia
                   -Recurring infections
                   -Ricter’s transformation

             CLL: Treatment
                   -Chlorambucil, with or wihtour corticosteroids
                   -Nucleoside purine analogues, especially fludarabine
                   -The monoclonal antibody, rituximad, alone or with
                   fludarabine
                   -Bendamustne: an older European ‘designer’ drug, now
                   showing promise on our side of the Atlantic
                   -The monoclonal anti-CD52 (alemtuxumab, Campaht-1H) in
                          refractory disease
                   -Allogeneic bone marrow transplantation in the rare case of
                   the young pt.

CLL: Managing the Complications
      -Impaired Immunity
            1.) Vaccinations
            2.) Prompt instituation of antibiotics
            3.) Gammaglbulin infusions if needed
            4.) Watch out for herpes zoster and tx it right away please!
            5.) Rarely prophylactic abx/fungals
      -Anemia
            1.)Is it autoimmune?
                     -Retic ount and Coomb’s test
                     -Corticosteroids and referall quickly
       2.) Non-immune: Consider regular EPO injections, don’t forget the
       other causes of anemia
-Thrombocytopenia
       1.) Splenic sequestrations: take it out
       2.) Hypoproliferative state: may need to repeat a bone marrow and
       then tx the CLL first and foremost
       3.) Hyperproliferative state: this is ITP.
               -Tx. It with corticosteroids, GG, splenecotmy and rituximab


2. Prolymphocytic Leukemia
        •Average age is 70, slightly older than classic CLL
        •Splenomegaly but not lymphadenopathy is common
        •The lymphocytosis is often >100,000 at presentation
        •20% are T-cell origin
        •Median survival is three years vs. 8 years with classic CLL
        •Most forms of therapy offer short term benefit

 Diagnosis: Prolymphocytic Leukemia
      •The peripheral smear shows larger lymphocytes with open
      chromatin pattern, one nucleoli and more abundant blue cytoplasm
      •Flow cytometry CD5+ and CD 19+
      •But, the presence of normal surface immunoglobulins indicates a
      more developmentally mature cell


3. Hairy Cell Leukemia
        •Often presents in older patients with fatigue, an infection,
        pancytopenia and a big spleen
        •4:1 male to female predominance
        •The pathologist or tech may see the characteristic cells
        •A bone marrow often reveals a “dry tap” due to the reticulin
        abundance
        •Lymphadenopathy is less common than in classic CLL
        •Diagnosis: Hairy Cell Leukemia
               •Lymphocytosis in the peripheral blood with cytoplasmic
               projections
               •Bone marrow biopsy is helpful showing “fried egg”
               appearance in tissue sectioning
               •IHC staining with acid phosphatase is strong and not inhibited
               by tartrate: TRAP
               •CD 5(-) and CD 19 +, with CD 11c separate this from CLL-
               classic
        •Treatment of Hairy Cell Leukemia
               •Before effective chemotherapy, splenectomy or nothing was
               the best route often for many years
                •1980s: alpha interferon, deoxycoformycin and
                2chlorodeoxyadenosine were born and changed everything
                      •Now survival approaches age-matched controls!!

4. Large Granular Lymphocytosis-General is CRAZY says we don’t need grunt
cells!

         •Is it LGL or is it Felty’s Syndrome
         •In LGL there is a predominance of lymphocytosis, coupled with
         neutropenia, splenomegaly and often RA features in as many as one-
         third
         •Felty’s Syndrome is more typically a rheumatologic condition with
         splenomegaly, neutropenia and lymphocytosis. (debate continues as
         to whether these are two diseases, or one)
         •Diagnosis: large granular lymphocytosis
                 •Previously called T-cell granular lymphocytic leukemia
                 •Peripheral blood shows lymphocytosis with large, eccentric
                 nuclei and azurophilic granules in abundant cytoplasm
         **TQ**•Neutropenia is common
                 •Flow cytometry shows post-thymic T-cells with CD 3+, CD 4 –
                 and CD 8 +, CD 57 +
                 •RF + in 60% of patients

         •LGL: treatment
                •None
                •Average lifespan greater than a decade
                •Neutropenic infections the most troubling feature
                •Antibiotics
                •Rheumatology consult

                •Cyclosporine
                •Methotrexate plus prednisone
                •CSFs not terribly helpful
                •Transfusions
                •Splenectomy
                •?alemtuzumab


 5. Adult T-cell Leukemia/Lymphoma-
         -Virally mediated causes

         •Human T-cell Lymphotropic virus, type 1
         •Southwestern Japan carries the highest prevalence, but also the
         Caribbean, tropical Africa, South America and Oceania
         •10 to 20 million people world-wide, but 2-5% develop the disease
         •Transmission of this retrovirus is mother-to-child in breast milk,
         sexual transmission, and blood-borne.
     ATL/L
           •Diagnosis: CD 4+ neoplastic cells, polylobated “flower” cells,
           lymphadenopathy, hypercalcemia, skin involvement
           •Clinical course varies from smouldering, untreated disease, to a
           rapidly progressive leukemic state and death. Cure is rare.
           •In Oncology, Dec. 2009 article there were twenty-three different
           drugs in clinical trials, trying to thwart this disease.


     Topic Three: Myelodysplastic Disorders UGLY MARROW!!

•MDS
    •Myelodysplastic Syndromes
    •13,000 per year in the U.S.A.
      •A disease of our elderly, and a few young people
    •“Ineffective” hematopoiesis
    •Two forms:
          –Primary: no known inciting agent
          –Secondary: due to prior exposure to toxin, especially chemotherapy
          alkylators, benzenes
    •Etiology:
          –Of the secondary forms, there are links to benzene workers, cancer
          chemotherapy survivors who received alkylators/XRT, congenital
          disorders like Fanconi’s Anemia and Bloom Syndrome, and perhaps viral
          stimulation.
    •Symptoms:
          –Fatigue, malaise
          –Recurring infections
          –Easy bruising
          –None (a typical consultation in my office is an elderly person with
          leukopenia found on the yearly check up)
    •Signs:
          –Pallor
          –Petechiae/purpura
          –Splenomegaly, rare
          –none
    •Laboratory analysis:
          –CBC reveals one, two or three cell lines depleted
          –Peripheral smear: macrocytic red cells, hyposegmented white cells
          (Pelger-Huet anomaly), thrombocytopenia
          –Bone marrow aspirate with cytogenetics is essential
    Imposters! DDx
             •Severe nutritional deficiencies
             •Alcoholism
             •Patients already on chemotherapy agents
             •HIV, untreated
              •Many seizure medications
              •Aplastic anemia

•The hallmark is disordered maturation of all three cell lines **TQ**
•Marrow cellularity is increased, but the peripheral counts are decreased
•This is the essence of ineffective hematopoiesis: “lots of tenants, but no one paying
     their rent”

•MDS: an old, but much used classification system
    •Pathology:
          –FAB (French-American-British) Classification
          –2 subgroups have < 5% marrow myeloblasts: RA, RARS. These typically
          have a long clinical course, requiring multiple transfusions and rare
          evolution into a leukemic phase
          –2 subgroups have > 5% marrow blasts: RAEB with 6-20% blasts, RAEB-
          T with 21-30% blasts. (kind of useless information)
             •The fifth type, Chronic Myelomonocytic Leukemia or CMML, mimics
             the myeloproliferative disorders, with increased peripheral white
             cells, and splenomegaly, but is Ph Chromosome negative. The
             “easy” way to tell them apart is the monocytosis on PBS.
             •Dysplasia is part of CMML, not CML

•Therapeutic options:
      –Allogeneic stem cell transplant is the only curative therapy known, and
          reserved for the “young” and excellent performance status
      –Supportive care/transfusions are the backbone of treatment
      –Erythropoetin
      –Induction chemotherapy, ala acute leukemia
•MDS: epigenetics
    •In many cases, there is no obvious alteration in the DNA genetic code.
    “Epigenetic” alterations occur with apparently normal cytogenetics, but with
    junk stuck to promoter sites involved in transcription. This cellular junk is
    often methylation, or histone de-acetylation. De-methylators, and Acetylators
    probably allow transcription to move forward in genes critical to cell
    maturation/apoptosis.

•MDS: palliation
    •There is a growing list of palliative drugs that can alter the clinical course, and
    transfusion dependence, without stopping the relentless migration to marrow
    failure
      –Dacogen or decitabine is a hypomethylation agent, given intravenously, has
           shown an improvement in transfusion dependence
      –Vidaza or 5 azacytidine acts in a similar manner, also intravenous, but given
           for a week straight once each month. Has shown a survival advantage.
      –Revlimid or lenalidomide is a cousin of thalidomide and only seems to work
           on MDS with 5q- mutation. This drug, especially, makes me do more
           bone marrow biopsies in 90 year olds.
•5q Minus Syndrome: del(5q)
         •With the loss of a section of the long arm, there is loss of diploid alleles,
         and the culprit in this form of MDS is thought to be the haploid state of
         SPARC, or “secreted protein, acidic, cysteine rich.” In vitro, lenolidomide
         will upregulate SPARC erythroblasts deficient in 5q. And in patients,
         transfusion independence is the usual result of using this oral drug.


           Topic Four: The Acute Leukemias

CRAZY FAST PROLIFERATION!
•Myeloid
•Lymphoid


•Acute Myeloid Leukemia
    •A clonal expansion of immature myeloid cells in the marrow and usually the
    peripheral blood
    •There is increased marrow expansion, and increased circulating myeloid
    cells…blasts and other early forms
    •This is a “bolt out of the blue” malignancy
    •Etiology:
          –Secondary forms previously discussed (arising out of MDS/AML)
          –Primary AML is caused by one of many mutations in the myeloid stem
          cell.
          –The typical inducers of mutations include radiation, chemotherapy,
          benzene, HTLV-1 infection, randomness
    •Symptoms and Signs
          –fatigue, recurring infections, bleeding, weight loss, thrombosis,
          confusion, dyspnea
          –Petechiae, mucosal bleeding, fever, altered mental status, pallor, tender
          nodules of neutrophilic origin called “Sweet’s Syndrome”
          –The typical presentation is an hysterical call from the ER or primary
          care physician letting me know a “hot leuk’ is on the way to the office.
    •Laboratory analysis:
          –CBC is NEVER normal and ranges from pancytopenia, to “white blood”
          with WBC over 100,000
          –The peripheral smear is terrifying, when you have once seen it. Blasts
          are everywhere, and normal cells few if any. The Auer rod clinches it!
          –Chemistries are needed, especially ‘lytes, creatinine, phos, uric acid,
          LDH
          –Coags may be out of order, espcially in APML
    •Bone Marrow Aspirate and Biopsy:
          –A requirement before therapy is started except in life-threatening
          situations
          –Histochemical staining with myeloperoxidase, esterase and periodic
          acid-Schiff help differentiate myeloid, monocytic and lymphoid cells of
          origin
           –Flow cytometry does it better, and often faster, if you have one
           available to you
     •Classification: FAB and WHO
           –FAB relies on staining and morphology and is widely used, especially
           older oncologists!
           –WHO, also uses morphology and stains, but incorporates flow
           cytometry and cytogenetics. Also uses 20% bone marrow blasts as a cut
           off for AML

•AML: FAB
    •M0              minimal differentiation, no Auer rods or granules
    •M1              without maturation, >50% have Auer rods, a few
                     promyelocytes appear
     •M2             with maturation, >70% Auer rods
     •M3             also acute promyelocytic leukemia, lots of granules, few Auer
                     rods
     •M4             myelomonocytic, lots of monocytes, and occasionally excess
                     eosinophils
     •M5             clear monocytic differentiation, few Auer rods, often with
                     hyperleukocytosis
     •M6             erythroleukemia, DiGuglielmo’s disease, poor prognosis
     •M7             megakaryocytic leukemia, look for marrow fibrosis, blasts
                     mark for megakaryocytic antigens, also poor prognosis


•AML: WHO
    •Likely to grow longer every year, and for now has FOUR main groups.
    • First category is AML with recurrent genetic abnormalities:
           –t(8:21)
           –inv(16) AML with eosinophilia
           –t(15:17) also known as APML
           –11q23
    • Second category is AML with MDS-related features:
           –Cases that fit AML (>20% blasts) but no prior cytotoxic exposure
           –Must have any of the following three features, previous MDS
           documented, typical cytogenetics of MDS in marrow or multilineage
           dysplasia
    •Third category is therapy-related myeloid neoplasm (t-MN)
              •Includes both AML, MDS and MDS/MPN
              •Increasing size of this category due to the “success” of modern
              chemo- and radio-therapies
              •50% hematologic malignancies, 33% solid tumors, the rest
              benign/chronic diseases requiring cytotoxic treatments to control
    •Fourth category is AML not otherwise specified
              •You guessed it- everything else!
              •In a very clever nod to history, this category uses the FAB general
              schema
              •AML with minimal differentiation, M0
              •AML without maturation, M1
              •AML with maturation, M2
              •AMML, M4
              •Acute monocytic leukemia, M5
              •Acute erythroid leukemia, M6
       •Acute megakaryoblastic leukemia, M7

•AML: management
    •Speed is of the essence
    •If your facility does not treat acute leukemics, then get on the phone now.
    •Before transfer you can get baseline labs, CXR, urine and blood cultures,
    coagulation tests for baseline, and start a good peripheral line
    •Broad spectrum antibiotics at the first sign of fever, or chilling (after you get
    the cultures!)
    •Give a dose of PO allopurinol
    •After you have received this patient at the tertiary care center…
          –Neutropenic precautions
          –Triple lumen central access
          –MUGA or echo in older patients
          –Alert the blood bank that you will need leukoreduced, irradiated, CMV
          negative products
          –Begin hydration to alkalinize the urine
          –More allopurinol
          –Infectious Disease consultation early on/antifungal prophylaxis
          –Others: dentistry, HLA typing, fertility counseling

•AML: emergencies!
    •Hyperleukocytosis: > 100,000 WBC usually, occurs as blasts are less
    deformable in the microcirculation and cause various forms of tissue ischemia.
    Organs start to fade: pulmonary infiltrates, rising creatinine. Treatment
    includes fast acting cytotoxic medications like hydrea, leukopheresis, and CNS
    irradiation in extreme cases
    •Tumor Lysis caused by precipitation of calcium phosphate and uric acid
    crystals in renal tubules. This is avoidable, usually, with a steady supply of
    alkyline IV, plus allopurinol, and maintaining urine output of > 100 cc per hour.
    Raspuricase is a proteolytic enzyme capable of degrading uric acid, and is NOT
    prevention, rather is treatment once the UA is too high.
    •DIC, disseminated intravascular coagulopathy is most specific to APML or in
    severe septicemia. This is a result of massive tissue factor activation of the
    cascade, followed by massive activation of the plasminogen/fibrinolytic
    pathways, ending in collapse of both systems, hence chaos.
              •As in any case of DIC, treat the underlying condition
              •Everything else is supportive and chasing your own tail. Give
              platelets and plasma products for bleeding. Anticoagulants if
              thrombosis is the main issue
              •All-trans retinoic acid, ATRA, is a simple molecule that does one thing
              in the human body and that is to cause differentiation of early myeloid
              precursors into more mature forms.
              •In APML, t(15:17), and knowing that DIC is either here or soon here,
              begin ATRA before induction chemotherapy, to cause the
              promyelocytes to differentiate into myelocytes, and prevent DIC on
              cell lysis(at therapy).
AML: therapy
    •Patients are now divided into good, intermediate and bad risk subsets at the
    outset.
           –e.g. GOOD = t(8:21), inv 16, t(15:17)
           –e.g. INTERMEDIATE = normal cytogenetics
           –e.g. BAD = 11q23, del5q-, trisomy 8
    •Treatment hasn’t changed (much) since I was a fellow (1988)
    •7 + 3 is the standard induction; a seven day infusion of ara-C and three doses
    of an anthracycline, typically Idarubicin
    •“Remission” is not cure
    •CR is in excess of 80% and 5 year survival >50% in good risk patients. (20%
    overall)
    •Remission rates, and long term survival falls precipitously for others, and the
    elderly, and those arising as secondary to some other disease.
    •High dose Ara-C is typically given for 3 to 4 more cycles in consolidation
    •HLA typing of family members, (MUD), gives one more avenue of hope.
    Allogeneic transplant offers cure and is used “upfront” in high risk patients,
    with transplant as relapse in others.
    •At relapse, more chemotherapy is the general rule, with Mylotarg,
    gemtuzumab, an antibody to CD 33 as another less toxic option

Acute Lymphocytic Leukemia
    •Maddeningly also called Acute Lymphoblastic, or Acute Lymphoid Leukemia
    •Only about 1000 cases per year in adults in the US, but the most common
    leukemia in children
    •20/80 vs. 80/20 Over simplified, but cure rates in adults are the inverse of
    children.
    •Symptoms and Signs
          –The twin peaks tell all. One group of patients afflicted are under 10 and
          the second over 50.
          –Children will often complain of bone pain
          –CNS penetration is a major issue with ALL, with meningeal signs
          possible, CN deficits, altered mental status
          –Lymphadenopathy is more common than with AML
    •ALL: laboratory analysis
             •The CBC will be abnormal
             •BM Biopsy and aspirate with histochemistries, flow cytometry and
             cytogenetics are essential
             •“chunky” positivity of PAS in IHC
             •Recall Philadelphia chromosome + CML can blast off into whatever it
             likes, including ALL. (25% of adults, but only 3% of children.) Impress
             your attending with is tidbit.
    •ALL: classification
             •FAB vs. WHO again.
             •FAB lists three subtypes
                      –L1 small cells with homogeneous chormatin
                      –L2 large heterogeneous cells, irregular cytoplasm
                      –L3 large homogeneous cells, with deep blue cytoplasm
•ALL: French-American-British (FAB) Classification




•ALL: WHO classification
       •Two general categories
             • Precursor B- cell ALL/lymphoma
             •Precursor T-Cell ALL/lymphoma
             •Clinically if there is a mass and <25% blasts in the marrow it
             is a lymphoma, and leukemia if the opposite.
             •Large clinical overlap, and treated the same

 •ALL: Goals of Therapy
       -Reinstate normal hematopoiesis
       -Eliminate minial residual disease
       -Prevent emergency of resistant clones
       -Provide prophylaxis to sanctuary sites

 •ALL: therapy
        •The foundation of therapy for ALL echoes AML
        •CNS prophylaxis is a mainstay of therapy with intrathecal
        infusions/Ommaya reservoir placement
        •4 and 5 drug “recipes’ have not changed much in 25 years.
        Vincristine and Prednisone are the backbone, plus, asparaginase,
        anthracycline and cytoxan
        •Induction, followed by Consolidation, followed by Maintenance
        chemotherapy. Favorites differ by institution and training, and all
        work similarly
        •Allogeneic transplantation is offered for high risk patients and at
        relapse
      •ALL: Phases of Treatment




•ALL: Multiple Drug Regimens




    •ALL: prognosis
            •More than 80% of children who achieve complete remission, and
            complete consolidation/maintenance therapy over a two to three year
            period, will be cured of their disease
            •Since the 1970s, there have been thousands of children grow up to
            be adults after this terrifying experience.
            •As with all cancer survivors there can be a price to pay in terms of
            fertility, secondary malignancies and growth/maturation changes.

				
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