Pathology Flashcards by Lauren Gruenebaum

T/F: In severe illness such as a heart attack, pneumonia, etc, we should work the patient up for diabetes.

FALSE!!!!

Stress of illness often raises glucose to high levels. DO NOT work up for diabetes!

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Bilirubin is a _____ function test.

liver

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______ is derived from aging and circulating RBC’s, less so from ineffective erythropoiesis and the turnover of other heme‐rich cells (including hepatocytes)

Bilirubin

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Increased indirect bilirubin may indicate what? (5)

MC: hemolysis
Common in newborns due to immature livers, hemolysis from ABO Ab
Sickle cell and spherocytosis pts (have mild lifetime jaundice)
Gilbert’s syndrome (fasting increases it more)
Rifampin
Trauma pts: reabsorpt. of hematoma; Medical pts: reabsorpt. of a hemorrhage w/in a lung infarct

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These “liver function tests” reflect liver disease or obstruction / cholestasis rather than liver function. Interpret with caution and insight! What are they? (4)

AST
ALT
Alkaline phosphate
LDH

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LDH (LD) is found in all tissues and increased values suggest nonspecific disease (ex: tumor marker for some germ cell cancers)
-HIGHEST LDH’s are in what? (2)

infectious mononucleosis

- megablastic anemias (intramedullay hemolysis)

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What can affect the serum potassium? and therefore it is critical to draw the specimen properly and be aware of this when interpreting the results.

Any hemolysis!

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When is the anion gap decreased?

multiple myeloma (cationic paraprotein)
hyponatremia, hypoalbunemia
bromide ingestion (anion)

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What is synthesized in the liver by macrophages and fat cells in response to inflammation? What is it useful in determining?

High sensitivity C-reactive Protein

heart disease/cardiovascular risk

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Leukocytes (WBC) polymorphonuclear cells (granulocytes) include what types of cells? (3)

neutrophils (segmented nucleus)
basophils (dark blue granules)
eosinophils (bilobed nuclei)

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What do blasts (even just 1) indicate if seen in the peripheral blood?

Disease!!! (immature cells of undifferentiated lineage)

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In adults, what is the reasonable range value for healthy WBC/mcL?

4500-11,000 WBC/mcL

17,000 for a three‐year old and 13,000 for a teen are reasonable upper limits

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What are the two types of agranulocytes (mononuclear cells) considered WBC?

lymphocytes

- monocytes (macrophages outside the bloodstream)

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TQ: A value of 8000 neutrophils/mcL is called…..

neutrophilia

an absolute neutrophil count above the top of the reference range

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TQ: A value of 2500 neutrophils/mcL is called…..

Neutropenia

serious infection is likely only with counts below 1000/mcL and grave danger only with counts below 500/mcL

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Neutrophilic bands are immature neutrophils. The presence of more than a few immature neutrophils in the peripheral blood is called what?

a left shift

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Increased eosinophils (greater than ___/mcL) may be due to what?

600mcL

meds
parasitic infx
Asthma
Hodgkin’s dz
Churg-Strauss!!!
Addison’s
higher in afternoon due to circadian rhythym of cortisol

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T/F: Pt’s with allergic or atopic disorders such as hay fever or other mild allergies don’t have elevated eosinophils

TRUE

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What is the reasonable reference range of lymphocytes for adults?

800-4800/mcL

higher in children and teens

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Activated lymphocytes such as atypical lymphocytes are found in what?
Depletion of CD4 cells is found in what?

infectious mononucleosis

HIV

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Are WBC lymphocytes increased or decreased in whooping cough?

increased

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What is the reference range for monocytes?

up to 900 mcL, 1200 for kids

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What is the volume of RBC to volume of whole blood called?

Hematocrit

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What are the reference ranges for hematocrit of an adult man and woman?

39-50% for men

35-46% for women

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In what conditions would RBC count be decreased? (4)

- anemia - microcytic normochromic - normochromic normocytic - macrocytic anemia.

In what conditions would RBC count be increased? (3)

- polycythemia vera - secondary polycythemia - vigorous exercise.

At what mean cell volume do most hemolytic anemias fall?

80-100 (normal range...normocytic)

What is the mean cell volume for macrocytic diseases such as megaloblastic anemia? Normocytic? Microcytic (iron deficiency and thalassemias)?

>100 macrocytic 80‐100 normal range, normocytic < 80 microcytic

______ anemias lack hemoglobin. The red cell tends to be pale and small because the RBC precursor cannot make enough hemoglobin

Hypochromic

What are some examples of hypochromic anemias? (3)

- Iron deficiency - Thalassemia - Severely defective porphyrin synthesis

What is increased in hereditary spherocytosis? (membrane fragments are lost so the hemoglbin is more dense and stains purply)

MCHC (Mean corpuscular hemoglobin concentration...a measure of the concentration of hemoglobin in a given volume of packed red blood cells)

RDW (red blood cell distrib) reference range is 11.5 to 14.5%. If the value is above this, what is suggested?

Anisocytosis (variation in size) note: may indicate the degree of poikilocytosis (variation in shape)

________ count is an indication of the responsiveness of the bone marrow to decreased RBCs.

Reticulocyte | Reticulocytes are immature RBC’s or some times called shift cells. They are larger than normal (7 μm) RBC’s

What are the small fragments of megakaryocytes that are released into the blood called? What do they aid in?

Platelets: they aid in clotting since they contain activators of coagulation

What is thrombocytosis? What is it due to? (7)

increased platelet count due to reactive conditions such as: - infections - iron def - splenectomy - hypothermia - myeloproliferative disorders - leukemia - polycythemia vera

When is platelet count decreased? (6)

- Incr/decreased destruction - pooling in spleen - immunologic mechanisms - drugs like heparin - dilutional coagulopathies - infection

- May raise the RDW - Problem with cytoskeleton or hemoglobinization - Extreme variation in shape and size - May occur after a transfusion in a pt with microcytic anemia

Poikilocytosis

- Measure of variation in RBC size - Just a marker that something's wrong - May occur after a transfusion in a pt with microcytic anemia

Anisocytosis

- Bizarrely-shaped red cells - Spectrin mutation - Autosomal recessive variant on hereditary spherocytosis

Hereditary pyropoikilocytosis

- These cells lack the central pallor, are small, round, and slightly darker in color - Cytoskeleton may be defective or portions of the membrane may have been removed >> weak, less deformable membrane

Spherocytes | "Hereditary Spherocytosis"

RBC acanthocytes are a famous marker for what?

abetalipoproteinemia

- Coarse granulation resulting from aggregation of RNA - A non-specific finding in anemia - Classic example = lead poisoning - Seen in Beta-thalassemias

RBC basophilic stippling

Lead inhibits the activity of what 2 enzymes involved in heme synthesis? How are ringed sideroblasts formed?

Delta aminolevulinic acid and ferrochelatase. Inhibiting ferrochelatase >> ringed sideroblasts (iron remains within the mitochondria of the red cell precursors rather than joining the globin chains to make Hb molecules)

What are Howell-Jolly bodies? If you see these, the pt may not have what organ? What kind of anemia do you see Howell-Jolly bodies?

- Howell-Jolly bodies are fragments of nuclear material (DNA) in RBCs. - Pt may not have a spleen, which typically removes them quickly. - Hereditary spherocytosis (normocytic anemia with predominantly extravascular hemolysis)

In a blood smear, how could tell which cell is "polychromatophilic?"

It will be appear more purple because it hasn't lost all of its purple-staining RNA.

- A spherocytosis variant | - Normal in camels, llamas, alpacas

Ovalocytes (elliptocytes)

Target cells. Think...

Hemoglobinopathy

Teardrop cells...

Something replacing the marrow.

Intracellular ring forms make the diagnosis of what?

Malaria

- Intra- AND extracellular rings helps to differentiate this protozoan from malaria. - Use ticks as reservoir

Babesia

- Elongated and pale cells | - Seen in true iron deficiency anemia

Pencil cells

Iron-laden mitochondria seen in what? | The mitochondria are termed what?

Sideroblastic anemia iron-laden mitochondria = Pappenheimer bodies

Paroxysmal cold hemoglobinuria causes what to happen between RBCs?

Agglutination

Rouleaux formation (coin-stacking of RBCs) is suggestive of what?

Plasma cell dyscrasia / myeloma / paraproteinemia

96% of a normal adult's Hb is: 3% of a normal adult's Hb is: 1% of a normal adult's Hb is:

(96%) HbA = 2A + 2B (3%) HbA2 = 2A + 2D (1%) HbF = 2A + 2G

What are the 4 alpha chain shortages seen in alpha-thal?

1 gene deleted: asymptomatic 2 genes deleted: cis = worse, risk of severe thal in offspring, Asians ... trans = Africans 3 genes deleted: 4B = HbH 4 genes deleted: 4G = Hb Bart's

What is the sequence of RBC precursors? (5)

- Pronormoblast - Basophilic normoblast (prorubricyte) - Polychromatophilic normoblast (rubricyte) - Orthochromatophilic normoblast (metarubricyte) - Reticulocyte ("young reds") – nucleus is exported before this step

How would you discriminate a pronormoblast from other RBC precursor cells in a blood smear?

Pronormoblast: - Large, circular cell housing a large, circular nucleus - Thin rim of cytoplasm around the nucleus

Describe how anemia presents clinically.

Anemia presents with signs and symptoms of hypoxia: - Weakness, fatigue, malaise, dyspnea - Pale conjunctiva and skin - Headache and lightheadedness - Angina, esp with preexisting CAD

What 3 things do you watch for when diagnosing hemolytic anemias?

- Reticulocytosis - Incr indirect bilirubin - Incr LDH

- Inherited defect of RBC cytoskeleton-membrane tethering proteins - Membrane blebs are formed and lost over time – loss of membrane renders cells round ("spherocytes") instead of disc-shaped ... spherocytes are less able to maneuver through splenic sinusoids and are consumed by splenic macrophages >> anemia

Hereditary spherocytosis

- Spherocytes with loss of central pallor - Incr RDW and incr MCHC (dark color) - Splenomegaly, jaundice, and incr risk for bilirubin gallstones (extravascular hemolysis) - Incr risk for aplastic crisis with parvovirus B19 infection of erythroid precursors

Hereditary spherocytosis

Hereditary spherocytosis is diagnosed with what test?

Osmotic fragility test – reveals increased spherocyte fragility in hypotonic solution

What are reticulocytes?

Young RBCs released from the bone marrow | -Identified on blood smear as larger cells with bluish cytoplasm (due to residual RNA)

What are Heinz bodies? | A deficiency in what enzyme will cause Heinz bodies to precipitate?

Denatured Hb that is often attached to the membrane G6PD deficiency

How are Heinz bodies removed from RBCs? | What kind of cells result from their removal?

Heinz bodies are removed from RBCs by splenic macrophages, resulting in "bite cells."

- X-linked recessive disorder resulting in reduced half-life of G6PD; renders cells susceptible to oxidative stress - Oxidative stress (e.g., fava beans) precipitates Hb as Heinz bodies - Presents with hemoglobinuria and back pain hours after exposure to oxidative stress

G6PD deficiency

- AR mutation in ß chain of Hb - Normal glutamic acid (hydrophilic) is replaced with valine (hydrophobic) - Gene carried by 10% of individuals of African descent (likely due to protective role against falciparum malaria) - Arises when 2 abnormal ß genes are present >> >90% HbS in RBCs

Sickle cell disease

What happens to HbS when it gets deoxygenated? | What kind of cells does this result in?

- HbS polymerizes when deoxygenated | - HbS polymers aggregate into needle-like structures >> sickle cells

Which Hb prevents sickling?

HbF | -therefore children do not show symptoms for the first few months of life

What 3 things precipitate sickling?

Hypoxemia Dehydration Acidosis

- Leg ulcers - Strokes - Retinal infarcts - Priapism - Painful bone infarcts - Thrombosis - Pain management

Sickle cell disease

You see autosplenectomy in what disease?

Sickle cell disease

Acute chest syndrome (vaso-occlusion in pulmonary vasculature) is the MC cause of death in adult pts of what disease?

Sickle cell disease

Massive erythroid hyperplasia ensues from sickle cell dz, leading to what 3 things?

- Expansion of hematopoiesis into skull ('crewcut' appearance) and facial bones ('chipmunk facies') - Extramedullary hematopoiesis with hepatomegaly - Risk of aplastic crisis with parvovirus B19 infection of erythroid precursors

Explain sickle cell trait. | What does this result in?

One mutated and one normal ß chain; results in <50% HbS in RBCs, therefore these pts are generally asymptomatic

In sickle cell trait pts, sickling is caused by what 2 things?

- Hypoxia (high altitude) | - Damaged renal medulla (electrolyte loss)

- AR mutation in ß chain of Hb - Normal glutamic acid is replaced by lysine at 6th AA position of ß chain - Less common than sickle cell dz - Presents with mild anemia due to extravascular hemolysis - Characteristic HbC crystals (rod-shaped) are seen in RBCs on blood smear - Mostly target cells in the blood

Hemoglobin C disease

- Result of the substitution of lysine for glutamic acid at the 26th amino acid of the ß globin chain (common in Asia) - Presents with mild microcytosis and target cells are seen

Hemoglobin E

4 ß chains are seen in what dz?

``` HbH disease (alpha-thal when 3 genes are deleted) ```

- Lots of little tiny red cells (MCV = 65 fL) - Mild anemia - Pancake cells - Maybe a few RBCs with basophilic stippling

Beta-thalassemia minor

- Normocytic, normochromic anemia with predominant intravascular hemolysis - Acquired life-threatening dz characterized by complement-induced intravascular hemolytic anemia - Occurs episodically, often at night during sleep when pH is lowest (activates complement) - Main cause of death is thrombosis of the hepatic, portal, or cerebral veins - Iron deficiency anemia may result from losing Hb into the urine

Paroxysmal nocturnal hemoglobinuria (PNH)

___ infection causes sickness and death largely (but not entirely) by damaging the immune system, leading to opportunistic Infections and unusual tumors / odd cell proliferations

HIV infection

____ produces consolidation of the lungs. The alveoli fill with micro-organisms with a limited or absent inflammatory response.

PCP Look like crushed ping-pong Produces no sputum !!!

PCP in combination with ______ in MSMs = first identification of AIDS. Linked to low CD4 counts (below 200)

Kaposi’s

A high-resolution CT scan of “PCP” shows what?

Ground-glass opacities because the alveoli are either packed or empty.

How do you dx PCP? Hint: what test?

Blood test! 1-3-beta-d-glucan component of pneumocystis wall May have to induce sputum to send to lab (biopsy, aspirate, etc)

_________ may be complication of HIV infx. Rates are growing due to homeless population and transmission from HIV pts.

Tuberculosis

- A consumptive coagulopathy due to abnormal coagulation | - Poikilocytosis, schistocytes, decr platelets, microcytes

Disseminated intravascular coagulation (DIC)

- Cancer association: Hodgkin, non-Hodgkin, thymomas - Systemic autoimmune dz – SLE, scleroderma, rheumatoid arthritis - Viral infections in children - Ulcerative colitis - Benign ovarian tumors, such as dermoid cysts

Hemolytic anemias | AHA warm

- Cold agglutinins are due to IgM antibodies - May be assoc with a lymphoproliferative disorder - Can be 1) Idiopathic; 2) Secondary to infection, mycoplasma, mono, others; 3) Paroxysmal cold hemoglobinuria IgG against P blood groups

Hemolytic anemias | AHA cold

What is the test that detects whether Ig and/or complement is coating the surface of the pt's RBCs? What is a (+) test?

Direct antiglobulin test ("Direct Coombs" or DAT) (+) test = agglutination of RBCs

What is the test that detects auto-antibodies or unexpected alloantibodies in pt's plasma or serum? What is a (+) test?

Indirect antiglobulin test ("Indirect Coombs" (+) test = agglutination

- An acquired disorder of nuclear maturation - High MCV, hypersegmented neutrophils, slight jaundice, high LDH - Deficiency of B12, folate, or both, which is essential for DNA synthesis - Pernicious anemia, inadequate intrinsic factor - PS: variable degrees of cytopenias, often pancytopenia - Hallmark feature = macrocytosis and oval macrocytes *** - RBC fragments, schistocytes and inclusions, such as Howell-Jolly bodies, basophilic stippling and Cabot rings

Megaloblastic anemia

Bone marrow findings in megaloblastic anemia:

- Trilineage megaloblastic changes - Nuclear-cytoplasmic dyssynchrony - Erythroid hyperplasia - Granulocytic hyperplasia

- A type of megaloblastic anemia in which the underlying cause is a defective intrinsic factor, which required for the absorption of vitamin B12 - Atrophic gastric parietal cells (supposed to make IF) - Rare in children

Pernicious anemia

- Low serum iron - High TIBC - Low % saturation - Low serum ferritin - Absent bone marrow iron *** - Microcytic, hypochromic and pencil cells - Pts like to chew ice cubes - Heavy periods, GI bleeding (hookworm), bad diet (junk food, vegans), malabsorption (famously sprue), achlorhydria

Iron deficiency anemia

27yo woman admitted with a hx of Crohn's dz. | Labs: WBC 11.16, RBC 4.03, Hb 8.0, Hct 28.7, MCV 71.0, MCH 20.6, MCHC 28.6, RDW 17.2

Iron deficiency anemia

What is the test that detects whether Ig and/or complement is coating the surface of the pt's RBCs? What is a (+) test?

Direct antiglobulin test ("Direct Coombs") | (+) test = agglutination of RBCs

- Normocytic, normochromic morphology early - Microcytic, hypochromic morphology *** - Hypo-regenerating, normocytic/normochromic morphology later on - High ferritin - Low TIBC * - Low serum iron - Low % saturation - Interleukins acting on liver to produce hepcidin, which prevents marrow macrophages from releasing their iron to developing RBCs - Causes today: osteomyelitis, TB, RA, leprosy, CF, bedsores

Anemia of chronic inflammation (disease)

- Selective decrease in bone marrow RBCs, without other associated cytopenias - PS: chronic normocytic to slightly macrocytic anemia - BM: normal cellular without erythroids - Incr EPO levels - Congenital causes, Diamond-Blackfan anemia

Pure red cell aplasia

- Occasionally produces infection of the cervical lymph nodes in healthy people, especially children. - Can present as single-site lymphadenitis.

Mycobacterium avium organisms (like TB or other non-TB)

- A common childhood viral infection ("fifth disease," "erythema infectiosum, "slapped face") - During illness, virus suppresses erythropoiesis - Cause of aplastic crisis seen in ppl with chronic hemolysis (spherocytosis, sickle cell disease)

Parvo B19

How do we diagnose CMV?

- Rise in complement-fixing antibodies (4-fold titer over 2-4 weeks) - Finding IgM 30% or more of IgG. - Like the more common and more familiar Epstein-Barr infectious mononucleosis, CMV travels by kissing.

- A family of genetic illnesses with a severe lack of erythroid precursors in the marrow from birth - Short stature, various craniofacial, thumb, and skeletal abnormalities - Incr HbF, EPO levels, RBC adenosine deaminase levels - RBC aplasia, decr reticulocyte count - Macrocytic anemia (MCV = 110-140)

Diamond-Blackfan anemia

- In contrast to Diamond-Blackfan, these ppl have plenty of RBC precursors, but they do not develop properly - Illness is characterized by megaloblastic changes in the BM along with ineffective erythropoiesis (dyserythropoiesis) due to lack of maturation as a result of mitotic defects - Macrocytic anemia - Anisopoikilocytosis, basophilic stippling, low reticulocyte count, and Cabot rings - CDA II may mimic PNH due to incr hemolysis

Congenital dyserythropoietic anemia (CDA)

- Toxoplasmosis is infection with the protozoan Toxoplasma gondii, which completes its life cycle in ___. - Avoid eating what?

cats (change the litter box!) avoid eating undercooked meat!

- An acquired disorder of nuclear maturation - Deficiency of B12, folate, or both, which is essential for DNA synthesis - Pernicious anemia, inadequate intrinsic factor - PS: variable degrees of cytopenias, often pancytopenia - Hallmark feature = macrocytosis and oval macrocytes *** - RBC fragments, schistocytes and inclusions, such as Howell-Jolly bodies, basophilic stippling and Cabot rings

Megaloblastic anemia

Causes of Mechanical Hemolysis (3)

- Old-fashioned heart valves - Impact athletes (long-distance runners) - Karate chopping and bongo drumming

- Pt who has Hb level above reference range and they're not dehydrated - May be secondary to chronic hypoxia, high-affinity Hb's, or anabolic steroid use by bodybuilders

Polycythemia

CMV in the colon was a common problem in which pts?

AIDS pts

T/F: Involvement of the brain in CMV infections is rare, but is devastating.

TRUE

If cryptococcosis is suspected, perform what first?

Neuroimaging | also look at CSF

__________ ________ was well-known, in the old days, as a sign that HIV infection was progressing to the late stage (“AIDS”). -Usually, the CD4 count will be below 100.

Esophageal candidiasis

Cryptosporidiosis is infection by C. hominis or C. parvum. -Protozoans live in what area of the body? What does this contribute to in AIDS pts?

- Brush border of the small intestine | - Diarrhea in AIDS pts

- Toxoplasmosis is infection with the protozoan Toxoplasma gondii, which completes its life cycle in ___. - Avoid eating what?

cats (change the litter box!) avoid eating undercooked meat

How does toxoplasmosis present? How can we dx it?

-Primary infection is usually asymptomatic, or may mimic infectious mononucleosis - Find anti-toxoplasmosis IgM without IgG in the serum - Tachyzoites are found on fine-needle aspiration of the enlarged lymph nodes.

How does toxoplasmosis appear in the brain?

Ring-enhancing lesions (often in the basal ganglia)

Toxoplasmosis remains latent in the body after infection, and HIV patients who have antibodies as well as CD4 counts below ____ are prone to develop

100

Toxo is famous for involving the retina. What does it look like?

white fluff, less hemorrhage than CMV retinitis

- Decr serum iron - Incr TIBC - Decr % saturation - Hypochromia and pencil cells - Pts like to chew ice cubes - Heavy periods, GI bleeding (hookworm), bad diet (junk food, vegans), malabsorption (famously sprue), achlorhydria

Iron deficiency anemia

27yo woman admitted with a hx of Crohn's dz. | Labs: WBC 11.16, RBC 4.03, Hb 8.0, Hct 28.7, MCV 71.0, MCH 20.6, MCHC 28.6, RDW 17.2

Iron deficiency anemia

A single, narrow-based bud, and a capsule describes what? Hint: Second most common cause of death in AIDS in Africa

Cryptococcus (C. neoformans)

Cryptococcus is related to which animal? Grows on which prep?

Pigeons! | India ink!

If cryptococcosis is suspected, perform what first?

Neuroimaging | also look at CSF

- An unusual bacterial infection due to immune compromise - Solid masses of bugs - Looks like bumps on skin

Bacillary angiomatosis

- Normocytic, normochromic morphology early - Microcytic, hypochromic morphology - Hypo-regenerating, normocytic/normochromic morphology later on - Interleukins acting on liver to produce hepcidin, which prevents marrow macrophages from releasing their iron to developing RBCs - Causes today: osteomyelitis, TB, RA, leprosy, CF, others

Anemia of chronic inflammation (disease)

Pure red cell aplasia

Progressive multifocal leukoencephalopathy (PML) involves which virus? What does it damage?

- JC papovavirus - Damages the brain - CD4 count usually <200.

Cryptosporidiosis is infection by C. hominis or C. parvum. Protozoans live in what area of the body?

Brush border of the small intestine | diarrhea in AIDS

Today, the lab can test for cryptosporidium. Easiest is examining the _____ – cryptosporidia are acid-fast and can be easily seen on microscopy

stool

Does histoplasma capsulatum have a capsule?

NO!

Birds, bat droppings, starling roosts...think

histoplasmosis fungus (2 micron yeasts) * (It’s estimated that only about 1 in 2000 people who meet histoplasmosis in the wild will get seriously sick, but the risk is greater if there’s a big dose (camping in starling territory, cavers getting into bat guano)

Aspergillosis commonly follows which infection?

pneumocystis pneumonia

Fruiting body, 45 degree branching

Aspergillus

Spirochetosis of the colon seen in which infection?

Aspergillus

T/F: Zoster can occur at any CD4 count

True

- Erythroviruses (______ __): usually produce a mild flu-like illness that may be followed with a rash and/or joint pain (“fifth disease” / “erythema infectiosum”). - Causes episodes of red cell production failure in folks with hemolytic anemias, or severe anemia before birth (“hydrops”)

parvo B19

- An unusual bacterial infection due to immune compromise - Solid masses of bugs - Looks like bumps on skin

Bacillary angiomatosis | Bartonella species

What are 6 acquired causes of pure red cell aplasia?

- Aplastic crisis - Parvovirus B19 - Malnutrition - Drugs (chloramphenicol is infamous) - Thymoma or rarely other neoplasms - Idiopathic

Parvo B19

- Due to defective DNA repair mechanism. Marrow stem cells are lost. - Multiple congenital anomalies - Trilineage, bone marrow failure, usually at an early age *** - Substantial increased risk for other malignancies

Fanconi anemia

Diamond-Blackfan anemia

_______ is dry or flaky scalp/skin. Likely to flare up as CD4 counts drop below 400, and become severe below 200.

Seborrhea

_____ ________– an Epstein-Barr virus effect in which the squamous epithelium on the tongue proliferates.

Hairy leukoplakia

Outbreaks are generally water-borne, including swimming pools and ponds, and are more common where there’s poor sanitation, and during the rainy season in the tropics.

Cryptosporidium

- Thermally-dimorphic fungus – a mold in the soil, a yeast at 37 degrees - The yeasts multiply in the lungs - Before they can do any real damage, they are surrounded and either killed or walled off by macrophages.

Histoplasmosis

- In contrast to Diamond-Blackfan, these ppl have plenty of RBC precursors, but they do not develop properly - Illness is characterized by ineffective erythropoiesis (dyserythropoiesis) due to lack of maturation as a result of mitotic defects - Macrocytic anemia - Anisopoikilocytosis, basophilic stippling, low reticulocyte count, and Cabot rings - CDA II may mimic PNH due to incr hemolysis

Congenital dyserythropoietic anemia (CDA)

Kaposi’s “sarcoma”, with pneumocystis pneumonia, led to the identification of AIDS and HIV What causes it? Where is characteristically located? What does it look like under microscope?

Infection with herpes 8 (KSHV) - Dark purple skin/mouth nodules in a pt with AIDS - On chest/back, the palate and tip of nose -Looks like granulation tissue (overgrowth of little blood vessels)

-These are cancers of the lymphocytes that grow as solid masses. -Many of them are much more common in HIV patients than in other folks

Malignant lymphoma

In the absence of EPO, the Hb level will drop to what?

around 8 gm/dL

- Present when the bone marrow is replaced by something that isn’t functioning marrow (TB, histoplasmosis, and cancer are the most familiar) - PS: nucleated RBCs, teardrop RBCs, young neuts

Myelophthisic process

Causes of Mechanical Hemolysis (3)

- Old-fashioned heart valves - Impact athletes (long-distance runners) - Karate chopping and bongo drumming

Pt who has Hb level above reference range and they're not dehydrated

Polycythemia

The result of antigen binding to IgE on the surface of mast cells and basophils. These instantly de-granulate and release active substances into the surrounding tissue.

Type I hypersensitivity "Anaphylactic" "Immediate"

- Immediately released from mast cells | - Makes vessels dilate and leak

Histamine

- Immediate response | - Contract smooth muscle and make vessels leak

Leukotrienes

- Immediate response | - Causes bronchospasm and much mucus production

Prostaglandin D2

The most important eosinophil attractant / activator is:

IL-5

A marker for NK cells is:

CD57

- Red, itchy swellings of the skin that blanch easily on pressure - Often, but not always, about IgE / Type I immune injury

Urticaria

Eosinophilic gastroenteritis. | Think...

Food allergy

Often due to massive IgE-mediated response

Anaphylaxis

- Lowering the temperature causes mast cells to de-granulate | - Not immune-mediated

Cold urticaria

- Due to wet heat | - Not immune-mediated

"Cholinergic" urticaria

Dendritic macrophages express IgE receptor (Fc[epsilon]RI) on their surfaces

Atopic dermatitis (aka eczema)

Type of hypersensitivity in which Abs attach to Ags on the surfaces of a cell (fixed Ag), and then something injures or destroys the cell

Type II hypersensitivity

Describe the Direct Coomb's test.

Use Coomb's reagent (Anti-IgG) to detect Ags present on the pt's RBCs (+) = agglutination

Caused by Abs against the basement membranes of lung and kidney

Goodpasture's disease

- Caused by Abs in the donor plasma against HLA Ags that the recipient has - Abs are often there because of a donor's previous pregnancy... hence the strong preference for plasma donors being men

Transfusion-related acute lung injury

MC cause of hypothyroidism from illness:

Autoimmunity

Adrenal gland being destroyed by T cells. | Think...

Addison's

- Islet of Langerhans being destroyed | - Both Abs and angry T-cells are generally present

Juvenile diabetes

- Abs cause hyperthyroidism by binding to and turning on the TSH receptors that drive thyroid hormone production - Abs cause proliferation of the loose connective tissue behind the eyes and on the shins

Graves disease

- Involves deposition of complexes of a soluble Ag and Abs, generally in vessel walls - These syndromes produce vasculitis (including possible infarcts), arthritis and/or glomerulonephritis

Type III hypersensitivity

Explain the Arthus reaction.

This is the model for localized immune complex-mediated tissue injury. Antigenic sensitization >> Ab formation >> Ag challenge >> Immune complex formation and inflammation

Explain serum sickness.

Antigenic sensitization >> Ab formation >> Re-exposure to Ag >> Immune complex formation and inflammation

- "Most hated of all Type III immune-mediated reactions" - Kidney may turn white and bloodless before surgeon's eyes as the vessels plug with complexes and fibrin ... IgG precipitates in glomeruli and arterioles

Hyperacute rejection of the donor kidney

- In this type of hypersensitivity, special T-helper cells (T(D)) programmed to recognize a particular "altered self" Ag are stimulated - Great for ridding body of virally infected cells, cells harboring intracellular parasites (TB, some fungi), and perhaps tumor cells - Also the way the body acute-rejects transplanted organs - T-cell mediated injury

Type IV hypersensitivity

What is anergy? | What does no response to an anergy test mean?

The lack of T(D) cell function. No response to anergy test = T-helper cell problem! Think sarcoidosis, lymphomas or other cancers, HIV infection, measles, or really bad disseminated infections.

What is the hapten in poison ivy?

Urushiol

What is a patch test used to confirm?

T-cell hypersensitivity (Type IV)

What is a halo nevus?

T-cells destroy melanocytes near a regressing nevus

Granuloma formation is often done by what kind of cells?

Th1 cells, no Ab required

TQ | Psoriasis rheumatoid arthritis, multiple sclerosis, Crohn's, ulcerative colitis, and sarcoid are examples of what?

T-cell mediated hypersensitivity (Th1 and/or Th17)

Acute cellular rejection occurs because of what type of cells?

CD8 cells

Acute humoral rejection occurs because of what?

Antibodies

- Type III immune injury (type II has already occurred) - When pt gets an allograft and already has Abs against it - IgG precipitates in gloms and arterioles - Fibrinoid in the arterial walls - Kidney blanched and ruined in minutes

Hyperacute rejection

- Rejection mediated by T-cells | - See "tubulitis" and "endothelialitis"

Acute cellular rejection

- Caused by Abs, with both Type II and Type III injury - Blood vessel intima takes most severe injury, and we see edema, fibroblast proliferation, myxoid change, and accumulations of foamy macrophages ("graft arteriosclerosis") - Look for C4d in the capillaries *

Acute humoral rejection

TQ - Usually seen in old allografts - Vessels are narrowed or totaled - Intima is most thickened and (unlike atherosclerosis) it tends to be concentric * - T-cells do cause thickening of intima / media

Chronic transplant rejection

TQ - Days to weeks after transplant - Often starts on the palms * - Generalized rash, sometimes loss of epidermis - Jaundice from damage to bile ducts - Ulcers along GI tract, may bleed - You'll only see a few donor lymphocytes, mostly CD8's

Acute graft-vs-host disease

- Appears later (after 100 days), more fibrosis and less obvious necrosis - Fibrosis of the dermis with loss of skin adnexal structures (resembles scleroderma) - Cholestatic jaundice from damage to bile ductules - GI damage with possible malabsorption and/or esophageal stricture - Damage to host T-cells, with immune compromise - CMV pneumonitis is the most feared infection

Chronic graft-vs-host disease

Defective Fas or FasL (apoptosis triggers) leads to a:

Lupus-like illness

The most-often-mutated gene in autoimmunity is:

PTPN22, a tyrosine kinase involved in lymphocyte responses.

- Immune system attacks the invader and the immune response then cross-reacts with something in the healthy tissues that resembles the microbe antigenically - E.g., strep cross-reacting with heart – rheumatic fever

Molecular mimicry

- Everyone keeps a few of their mother's cells - All mothers keep a few of the cells of the children they have carried - It is rumored that the cells are more abundant in people with autoimmune disease This is called:

Microchimerism

Anti-nuclear Abs: Rim pattern. | Think...

Classic systemic lupus | Anti-dsDNA **

Anti-nuclear Abs: Homogeneous pattern. | Think...

Drug-induced lupus

Anti-nuclear Abs: Centromere pattern. | Think...

CREST syndrome

Anti-nuclear Abs: Nucleolar pattern. | Think...

Scleroderma

- Anti-dsDNA - Anti-Sm (Smith) - Rim pattern on ANA

Systemic lupus

- Anti-ssDNA | - Anti-histone

Drug-induced lupus

Anti-Ro/SSA (Sjogren's A)

Neonatal lupus (heart block)

Anti-La/SSB (Sjogren's B)

Most Sjogren's pts, and many other folks

Anti-U1RNP (U1 ribonucleoprotein)

Mixed connective tissue disease (MCTD)

- Anti-Scl70 (anti-topoisomerase) | - Anti-RNA polymerase III

Scleroderma

Anti-centromere

CREST, the "milder version of scleroderma"

Anti-Jo (Jo1, transfer RNA synthetase)

Polymyositis / dermatomyositis

Anti-Mi2 (against a helicase that remodels nucleosomes)

Dermatomyositis, esp when the rash is present

Anti-SRP (signal recognizing polypeptide)

Polymyositis variant with severe necrotizing myopathy

- Anti-P155/TIF1(gamma) | - Anti-P140/MJ

Juvenile and paraneoplastic dermatomyositis

Must have 4 of these 11: - Butterfly (malar) rash - Discoid rash - Anti-dsDNA autoAbs - UV light triggers flare-ups (photosensitivity) - Oral ulcers - Arthritis - Serositis - Renal disorder - Neuro disorder - Hematologic disorder - Type II and Type III hypersensitivity (immune disorder)

Lupus

-Hematoxylin bodies -Adventitial onion-skinning -Immune complex deposits in a glomerulus (wire loop appearance) Think...

Lupus

A stripped nucleus opsonized by anti-nuclear Abs and now being devoured by phagocytes

LE cell | Think lupus.

What is the lupus band test?

Granular immunoglobulin and complement @ dermal-epidermal junction.

Mouth ulcers in lupus are due to:

Infarcts from vasculitis

- Sterile thrombi on the lines of heart valve closure | - May involve all surfaces of the leaflets

Libman-Sacks endocarditis in lupus

Many lupus pts are killed by:

Deep vein thrombi / pulmonary emboli

- Photosensitivity - Atrophy and scaling, esp in the center of lesions - Hyperkeratosis, hydropic change, lymphocytes

Discoid lupus

Which 3 drugs famously cause lupus?

Hydralazine Procainamide Isoniazid

The salivary and lacrimal glands fill with very angry lymphocytes. - Dry eyes - Dry mouth

Sjogren's syndrome

What is the most feared complication of Sjogren's?

Malignant lymphoma

- Autoimmune dz characterized by transient inflammation followed by dense fibrosis - Intimal layers of small blood vessels often undergo fibrous thickening - Almost always starts with Raynaud's (intimal thickening in finger artery) - Sclerodactyly - Calcium deposits - Telangiectasias at nail bases or on face - Pulmonary fibrosis - Initial abundance of CD4+ T-cells - Dense dermis, flattened dermal-epidermal junction, lost adnexal structures

Scleroderma | "Systemic sclerosis"

"Limited scleroderma" is known as:

CREST syndrome - Calcinosis (calcium deposits in skin) - Raynaud's - Esophageal fibrosis - Sclerodactyly - Telangiectasias

- Scleroderma-like changes in a patch | - Initial CD4+ T-cell-rich inflammation, then fibrosis and vessel changes (like scleroderma)

Morphea

- Variant of scleroderma - Scar contracts over 1/2 of face - Deformation of underlying skull

Parry-Romberg

- Tight skin with many eosinophils in the subcutis | - Remits after glucocorticoid tx

Eosinophilic fasciitis

- Onset of weakness in proximal muscles: "I have trouble climbing stairs." - Creatinine kinase and aldolase levels will be extremely high - Muscle and skin can calcify - Inflammatory arthritis and/or lung damage (usually interstitial fibrosis) - Upper esophagus involvement – swallowing may be a problem - Sometimes heart is involved

Polymyositis and Dermatomyositis

What is the difference between polymyositis and dermatomyositis?

Dermatomyositis has the characteristic rash (heliotrope color – light purple)!

In polymyositis, the distinctive lesion is extensive infiltration of muscle by:

CD8+ T-cells

In dermatomyositis, the lymphocytic infiltrate is within or near the perimysium and around the blood vessels. The infiltrate is a mix of what 3 cells? What membrane attack complex is often seen in vessel walls (unlike polymyositis)?

CD4+ T-cells B-cells Plasma cells Membrane attack complex = C5b-9

In dermatomyositis, where are the muscle fibers most atrophied?

At the edges of the fascicles

Gottron's sign on the knuckles is a marker for:

Dermatomyositis

"Mechanic's hands" | Think...

Polymyositis / Dermatomyositis / Anti-synthetase (Jo1) syndrome

- This illness is the best-known of the "overlap" syndromes "combining features of lupus, scleroderma, RA, and polymyositis." - Anti-U1-RNP Abs - Usually starts as synovitis of the fingers + Raynaud's - Sclerodactyly may occur as in scleroderma - Skin changes range from rash to calcification - Good response to glucocorticoids and kidneys are spared! - Aggressive dz, death is usually due to pulmonary vascular sclerosis ("pulmonary HTN") / pulmonary fibrosis

Mixed connective tissue disease (MCTD)

Characteristic features: - Fibrosis with a "cartwheel" pattern - Plasma cells making IgG4 in the lesion(s) - Increased IgG4 in the blood (2/3 of pts)

IgG4-related disease

3 tip-offs to vasculitis:

- Mononeuritis monoplex - Palpable purpura - Anybody who "you just can't tell why they are sick"

- "Migraine" - Vague aches and pains - Liver infarcts - Hep B/C and cryoglobulins as etiologies - Stroke and ballooning out of arteries (aneurysm) - Heart attack - Bowel infarcts - HTN - Gangrene - Peripheral nerve damage - Lungs spared! - Usually no hematuria - Patchy inflammation of all 3 layers of larger arteries; veins are spared! Fibrinoid change. - ANCA(–)

Polyarteritis nodosa, large-vessel type

- Vague aches and pains - Hemoptysis and infiltrates (lungs involved!) * - Stroke - Heart attack - Bowel infarcts - Nephritis / kidney failure - Gangrene - Peripheral nerve damage - Hematuria - Smaller veins and arteries show patchy 3-layer inflammation - p-ANCA(+) ** – positive anti-neutrophil cytoplasm test

Microscopic polyangiitis | small-vessel polyarteritis

- Caused by auto-Abs against proteinase 3 ** - Granulomas and patchy necrosis in arteries and veins - Destruction of the face - Episcleritis, "saddle nose" * - Lung cavities and bleeds - Permanent kidney damage - Gangrene - c-ANCA(+) **

Wegener's granulomatosis

- Purpura and IgA nephropathy - Arthritis - GI bleeding - Mild in children, severe in adults

Henoch-Schonlein purpura

- Marginally soluble protein precipitate in the cooler places and/or where blood is concentrated (i.e., kidney) - Another cause of vasculitis

Cryoglobulinemia

- Hallmark = abundant eosinophils in the peripheral blood and asthma - Mononeuritis multiplex very common - Vasculitis appears later; eosinophils abundant in vessel lesions - Often kills by occluding the microvasculature of the heart - Usually ANCA(+)

Churg-Strauss ("Allergic granulomatosis") ("Eosinophilic granulomatosis with polyangiitis")

- Autoimmunity against heat shock proteins - HLA-B51 *** - Mouth ulcers (always) ** - Eye lesions - Genital ulcers - Skin lesions - Neurologic symptom(s) - Infarcts of anything - Thrombosis of anything - Amyloidosis - "Pathergy" – 48hr after a needlestick, pt develops an ulcer or blister *** - Affects arteries and veins of all sizes

Behcet's dz

Amyloid is ____-_______ anything.

Amyloid is BETA-PLEATED anything.

Congo red with "apple green birefringence"

Amyloid

- Prolonged inflammation with macrophages | - Osteomyelitis, TB, leprosy, rheumatoid arthritis, etc.

Serum amyloid associated protein: Amyloid AA

Plasma cell neoplasia, not necessarily obvious

Immunoglobulin light chains: Amyloid AL

The bad forms have a mutation – may get a liver transplant

Transthyretin: Amyloid ATTR (AF)

- HLA light chains | - Longstanding kidney failure

ß-2 microglobulin: Amyloid ß2m (AH)

Heart with restrictive cardiomyopathy (stiff heart) may be due to:

Amyloid

Lardaceous spleen from amyloid in is the red or white area of the spleen?

Lardaceous spleen – WHITE area

One-organ amyloidosis hits where?

Tongue

- Best-known defect in phagolysosome formation and function *** - Neutropenia - Giant granules in leukocytes - Defective primary hemostasis - Albinism *** - Peripheral neuropathy *

Chediak-Higashi disease

Deficiencies of C2, C4, and especially Cq1 mimic:

Lupus

C3 deficiency causes serious problems with: (2)

- Bacteria | - Membranoproliferative glomerulonephritis

Deficiency in C5, C6, C7, C8, or C9 causes difficulty dealing with:

Bacteria, esp Neisseria

C1-esterase inhibitor deficiency produces:

Hereditary angioedema | -MC complement protein deficiency

Candida ("yeast"), later CMV, pneumocystis, etc. all indicate problems with:

T-cells

Bacterial infections once Mom's Abs clear indicates problems with:

B-cells

Baby has left arm paralyzed after receiving oral polio vaccine. Think...

Severe combined immunodeficiency (SCID)

Adenosine deaminase deficiency causes:

Severe combined immunodeficiency (SCID)

- Caused by lack of Bruton's tyrosine kinase (BTK), which lets B-cells mature - Bacterial, giardia, and enterovirus infections around 6 months of age - Must avoid live polio and MMR vaccines

X-linked agammaglobulinemia | "Bruton's"

- Lack of parathyroids - Lack of thymus - Midline cardiac defect(s) * - Hypocalcemia ***

DiGeorge syndrome / thymic dysembryogenesis

- Pts are unable to switch over from making IgM to making IgG, IgA, and IgE ** - Most often involves mutated CD40L gene **

Hyper-IgM

- Many diseases, low Ig's | - Lots of lymphoid tissue, with poor germinal centers

Common variable immunodeficiency (CVID)

You may never know you have it until your second blood transfusion. Anaphylaxis occurs and workup reveals that you're allergic to the donor's IgA.

Isolated IgA deficiency

- Mutant SH2D1A signal transduction protein is defective | - Allows Epstein-Barr virus to produce a deadly lymphoma-like overgrowth of lymphocytes, or destroy liver and/or marrow.

Sex-linked lymphoproliferative syndrome

- X-linked - Tiny platelets - Eczema - Deficient T cells - WASp locus

Wiskott-Aldrich

- At least three illnesses with lots of IgE and too little of other Abs - Faulty neutrophil movement - Most troublesome bacteria = Staph

Hyper-IgE | "Job's syndrome"

- Fungus that grows in the US Southwest and usually causes a mild lung infection when first encountered - A sphere full of yeasts (gumball machine) or hyphae with barrel-shaped spores may be seen in tissue during infections

``` Coccidioides immitis ("Coccidioidomycosis") ```

- "My worst case of the flu ever" - Sore throat, muscle aches, and otherwise resembling infectious mononucleosis - A rash and long duration may be tip-offs that it's actually:

Acute retroviral syndrome

Basophilia (4-5 basophils on high power field). Think...

Chronic Myelogenous Leukemia | CML

Basophilia is characteristic of: (4)

Chicken pox Small pox Nephrotic syndrome Basophilic leukemia (CML)

- WBC count > 50,000 uL - PS shows left shift (neutrophilic precursors in circulation) - Differentiated from leukemia - In non-leukemic neutrophilia, the LAP score rises with the WBC count

Leukemoid reaction

4 causes of leukemoid reaction:

- Severe sepsis - Burns - Tissue necrosis - G-CSF and GM-CSF therapy

Toxic granulation is due to: (5) What else can you see in these conditions?

- Cytokine release - GSF - Severe infection - Trauma - Burns Toxic vacuoles and Dohle bodies can be seen

- AR dz assoc with several different types of mucopolysaccharide disorders - An intense azurophilic granulation of the neutrophil cytoplasm

Alder-Reilly

TQ - AR disorder characterized by giant cytoplasmic granules - Affects all granulated cells and lymphocytes - Assoc with partial albinism

Chediak-Higashi syndrome

- Multiple blue-gray inclusions of variable size and shape in the cytoplasm of WBCs - Composed of endoplasmic reticulum - In May-Hegglin anomaly, giant platelets are also seen

Dohle bodies

Drug effects of G-CSF on PS and BM:

PS: toxic neuts, left shift, variable nuclear cytoplasmic dyssynchrony BM: hypercellularity primarily in the granulocytes

Drug effects of EPO on PS and BM:

PS: increased reticulocytes and occasional nucleated RBCs BM: hypercellular marrow with increased erythroids and their precursors

CD1:

Thymocytes and Langerhans cells

CD3:

Thymocytes and mature T-cells

CD4:

Helper T-cells, subset of thymocytes

CD5:

T-cells and a small subset of B-cells

CD8:

Cytotoxic T-cells, subset of thymocytes and some NK cells

CD10:

Pre-B cells and germinal center B-cells

CD19:

Pre-B cells and mature B-cells

CD20:

Pre-B cells after CD19 and mature B-cells

CD21:

EBV receptor; mature B-cells and follicular dendritic cells

CD23:

Activated mature B-cells

Progenitor cells have what cluster designation?

CD34

CD30:

Activation marker

All leukocytes have what cluster designation?

CD45

- Children and adolescents, episodic febrile illness, spontaneously regresses - Polyclonal hypergammaglobulinemia, massive LAD, effaced follicles, dilated sinuses, proliferation of histiocytes - No mitosis or necrosis

Rosai-Dorfman dz

3 variants: - Hyaline-vascular type: young pts, lollipops and onion-skinning, plasmacytoid monocytes - Plasma cell variant: older pts, anemia, thrombocytopenia, incr ESR, hyperplastic lymphoid follicles, interfollicular plasma cells with preserved sinuses - Multicentric variant: older pts, severe systemic symptoms, anemia, thrombocytopenia, incr ESR, IL-6, LDH, and C-reactive protein - All variants have polyclonal hypergammaglobulinemia - Assoc w/ POEMS, Kaposi's sarcoma, HIV - Hepatosplenomegaly

Castleman's dz

- EBV (HHV-4) infection resulting in lymphocytic leukocytosis with reactive CD8+ T cells (Downey cells) - Generalized LAD - Pharyngitis - Splenomegaly - Monospot test used for screening – detects IgM that cross-react with horse or sheep RBCs - Follicular hyperplasia, expanded paracortex, RS-like cells, dilated sinuses, foci of necrosis

Infectious mononucleosis (IM)

- Reactive paracortical hyperplasia of the LN - Incr DCs, Langerhans cells, and histiocytes with melanin deposits and lipid vacuoles - Often assoc w/ benign or malignant skin dz's. Follicular hyperplasia initially. - S100+ and CD1a–

Dermatopathic lymphadenopathy

- Diarrhea, wasting illness - LAD in multiple sites, foamy histiocytes in the sinuses and lymphoid areas - Caused by Tropheryma whipplei, a PAS+ bacilli with trilaminar walls

Whipple's lymphadenitis

- A necrotizing, granulomatous lymphadenitis caused by Bartonella henselae - U/L LAD, matted lymph nodes with necrotizing granulomas, central microabscesses with neuts, palisading epithelioid cells, and clusters of pleomorphic bacilli - B. henselae is (+) for silver stains and gram stains, or IHC

Cat scratch dz

- Intermediate-sized B cells (CD20); assoc w/ EBV * - Classically presents in a child or young adult (Afro American form = jaw; sporadic form = abdomen) - Translocation of MYC (Chr. 8) – t(8;14) is MC - Characterized by numerous mitotic figures and "starry-sky" appearance on microscopy

Burkitt lymphoma

- Large B-cells (CD20) that grow diffusely in sheets - MC form of non-Hodgkin lymphoma - Clinically aggressive (high-grade) - Presents in late adulthood as enlarging LN or extranodal mass - Arises sporadically or from transformation of low-grade lymphoma (e.g., follicular lymphoma) - CD20, CD30, CD79a, Ki-67 - If Ki-67 > 90%, Richter transformation is occurring

Diffuse large B-cell lymphoma

- Low-grade B-cell (CD20) neoplasm, composed of small lymphocytes that efface the lymph node and are seen in circulation as "butt or soccer ball" cells - Incr lymphocytes and smudge cells - High N/C ratio and dense chromatin - CD5, CD20, CD23, CD43 - May transform into diffuse large B-cell lymphoma (Richter transformation) - May develop autoimmune hemolytic anemia - MC leukemia overall

Chronic lymphocytic leukemia (CLL)

- Low-grade B-cell (CD20) lymphoma that expands the marginal zone - Assoc w/ chronic inflammatory states such as Hashimoto's thyroiditis, Sjogren's, and H. pylori infection - Monocytoid B-cells - Monotypic B-cells express IgM - slg

Marginal zone lymphoma (MZL)

- Small B-cell (CD20) lymphoma that forms follicle-like nodules - Presents in late adulthood w/ painless LAD - Driven by t(14;18) - CD10, CD20, CD22, BCL2, BCL6 - May transform into DLBC lymphoma

Follicular lymphoma

- Aggressive B-cell (CD20) lymphoma that expands the mantle zone - Presents in late adulthood with painless LAD - Driven by t(11;14) - Overexpression of Cyclin D1 facilitates neoplastic proliferation - Monomorphic cells efface lymph node - Commonly involves GI tract and BM - CD5+, CD23–, CD43+, Cyclin D1 (+)

Mantle cell lymphoma

- Small B-cell (CD20) neoplasm, usually involves BM, lymph nodes, and spleen - Dutcher bodies and lots of plasma cells - Expresses B-cell Ag's and Ig's - Assoc w/ Hep C and cryoglobulinemia *** - Waldenstrom's macroglobulinemia (IgM monoclonal gammopathy) seen in many cases

Lymphoplasmacytic lymphoma (LPL)

- Malignant proliferation of plasma cells in BM - Lytic (punched-out) lesions seen on x-ray, especially in vertebrae and skull - Elevated serum protein due to plasma cells producing Ig; M spike present on serum protein electrophoresis (SPEP) - Rouleaux formation - Primary AL amyloidosis - Proteinuria – free light chain excreted in urine as Bence-Jones protein

Multiple myeloma

- Plasma cell neoplasm - Solitary lesion in the BM cavity or in soft tissue - M-protein elevation

Solitary myeloma | "Plasmacytoma"

- MC type of myeloma - Incr serum protein w/ M spike on SPEP - M protein < 3 g/dL - Common in elderly - Patients are asymptomatic, but will eventually progress to multiple myeloma

Monoclonal gammopathy of undetermined significance | MGUS

- A single clone of plasma cells is responsible for overproduction of kappa chains or, rarely, lambda chains - Bence-Jones protein (light chain) found in the urine

Light chain dz

- Disorder in which Ig's precipitate out into the blood at low temps - They DO NOT agglutinate RBCs - Assoc w/ plasma cell dyscrasia, macroglobulinemia, hep C, SLE, RA

Cryoglobulinemia

What are the 4 Hodgkin lymphoma subtype CD markers?

CD15+, CD30+, EMA+, CD45–

In what plasma cell dz do we see M protein > 3 g/dL?

Smoldering myeloma

- Neoplastic proliferation of Reed-Sternberg (RS) cells, which are large B-cells with multilobed nuclei and prominent nucleoli ("owl-eyed nuclei") - Classically CD15+ and CD30+ - Often assoc w/ eosinophilia - Reactive inflammatory cells (T, B, and dendritic cells) make up the bulk of the tumor and form the basis for classification of subtypes

Hodgkin lymphoma (HL)

What are the 4 Hodgkin lymphoma subtypes?

Nodular sclerosis Lymphocyte-rich Mixed cellularity Lymphocyte-depleted

- MC of all Hodgkin lymphoma subtypes - Classic presentation: enlarging cervical or mediastinal lymph node in a young adult, usually female - Lymph node is divided into bands of sclerosis - RS cells present in lake-like spaces (lacunar cells) - Eosinophilia - CD15+, CD30+, EMA+, CD45–

Nodular sclerosis HL

- Best prognosis of all HL subtypes - Frequent mononuclear cells and RS cells - Background of T-lymphocytes - CD15+, CD30+, EMA+, CD45–, 40% EBV (+)

Lymphocyte-rich HL

- HL subtype that is assoc w/ abundant eosinophils (RS cells produce IL-5) - CD15+, CD30+, EMA+, CD45–, 70% EBV (+)

Mixed cellularity HL

- Most aggressive of all HL subtypes - Usually seen in elderly - Assoc with HIV/AIDS - -CD15+, CD30+, EMA+, CD45–, and most are EBV (+)

Lymphocyte-depleted HL

- Usually a large single tumor nodule - Neoplastic L&H cells (CD15–, CD30–, CD20+, LCA+, Oct2+, Bob1+, EBV (–) - CD3+ cells form rosettes around the neoplastic L&H cells ("popcorn cells") - Not part of the classical Hodgkin disease - Young males with cervical or axillary LAD, mediastinal dz

Nodular lymphocyte predominant HL

- Classic example = DiGeorge syndrome - Assoc w/ 22q11.2, giving rise to malformations of the thymus, parathyroids (hypoplasia), hypocalcemia, and diminished T-cell immunity - Also seen in SCID

Thymic hypoplasia

- Seen in myasthenia gravis and other autoimmune dz's | - May be mistaken for thymoma and unneeded surgery may be performed

Thymic hyperplasia

- A product of epithelial cells | - Usually composed of the medullary type epithelial cell (spindled or elongated in shape)

Non-invasive thymomas

- Benign neoplasm that's locally invasive but cytologically benign - Invasion occurs through the capsule into local structures surrounding the thymus

Invasive thymomas

- True carcinoma of the thymus - May be squamous cell carcinoma - May be a lymphoepithelial-like carcinoma

Thymic carcinoma

CD11c:

Granulocyte, monocyte, and macrophages | Also expressed on hairy cell leukemias

CD13:

Immature and mature monocytes and granulocytes

CD14

Monocytes

CD15:

Granulocytes and Reed-Sternberg (RS) cells

CD33:

Myeloid progenitors and monocytes

CD64:

Mature myeloid cells

CD16:

NK cells and granulocytes

CD56:

NK cells and a subset of T-cells

- Neoplastic accumulation of immature myeloid cells (blasts) - BM failure, anemia, thrombocytopenia/neutropenia - Increased blasts on PS > 20% - TdT+ - CD34, CD38, HLS-DR

Acute myeloid leukemia (AML) with minimal differentiation (M0)

- Neoplastic accumulation of immature myeloid cells (blasts) - BM shows > 90% blasts - May see some granules or rare Auer rods - MPO+, SSB+ > 3% - CD13, CD33, CD34, CD117, HLA-DR

AML without maturation (M1)

- Neoplastic accumulation of immature myeloid cells (blasts) - BM and PS show maturation of cells (> 20% blasts, > 10% maturing neutrophils, 3% - CD11b, CD13, CD15, CD23, CD33, CD65, HLA-DR

AML with maturation (M2)

- Neoplastic accumulation of immature myeloid cells (blasts) - Characterized by t(15:17), which disrupts retinoic acid receptor (RAR) ... RAR blocks maturation and promyelocytes (blasts) accumulate - Kidney bean-shaped nucleus - Short, thick Auer rods with stubby ends - Increased # of azurophilic granules - Strong assoc w/ DIC! - Tx: Vitamin A derivative

Acute promyelocytic leukemia (APL)

- Myeloid and lymphoid neoplasm with eosinophilia - Abnormalities of PDGFA, PDGFRB, or FGFR1 - Rare dz - Share a fusion of a tyrosine kinase gene *** - Characteristic eosinophilia - Deletion of chr. 4 FLIP1L1 - PDGFRA

AML eosinophilia

- Rare dz - Assoc w/ hyperhistaminemia due to increased basophils - Causes: allergic, inflammatory disorders, endocrinopathy, renal dz, infections, irradiation, carcinoma - CD11b, CD13, CD33, CD123, CD203

Acute basophilic leukemia

- A proliferation of both neutrophil and monocyte precursors, including promonocytes (> 20%) - MPO+, NSE+ - CD13, CD15, CD33, CD65 - CD4, CD11b, CD11c, CD14, CD36, CD64, CD163, lysozyme

Acute myelomonocytic leukemia

- Neoplastic accumulation of monoblasts (> 80%) - Blasts characteristically infiltrate gum >> Gingival hyperplasia *** - Hemophagocytosis may be seen - CD13, CD33, CD15 - CD4, CD11b, CD11c, CD14, CD36, CD64, CD163, lysozyme

Acute monoblastic and monocytic leukemia

- Proliferation of megakaryocytes - SBB–, CAE–, MPO– - May react with PAS, acid phosphatase and focal or punctate non-specific esterase - CD41 and CD61 ***

Acute megakaryocytic leukemia

- Another name for myeloid sarcoma or extramedullary myeloid tumor - Very rarely can these occur without pre-existing conditions - Usually assoc w/ other AML - Leukemia cutis = infiltration of the dermis by leukemic cells, granulocytic sarcoma

Chloroma

3 disorders seen: - Transient myeloproliferative disorder with large numbers of circulating blasts; GATA1 mutation - A true megakaryocytic leukemia; GATA1 mutation; ALL or AML can develop - An interval happens, then.....

Downs-related myeloid disease

- Neoplastic proliferation of mature myeloid cells, especially granulocytes and their precursors - Basophilia - Driven by t(9;22)(q34;q11.2), which generates a BCR-ABL fusion protein with increased tyrosine kinase activity * - No dysplasia is seen - Splenomegaly is common

Chronic myeloid leukemia (CML)

How do you know when CML has begun the transformed and progressive phases?

Blast count > 20% of the PS or BM.

- Neoplastic proliferation of mature myeloid cells, especially RBCs - Males: Hb > 18.5 .... Females: Hb > 16.5 - Assoc w/ JAK2 V617F mutation - Hypercellular BM - Low EPO - PS shows leukoerythroblastosis

Polycythemia vera

- Neoplastic proliferation of mature myeloid cells, especially megakaryocytes - Assoc w/ JAK2 kinase mutation (50% of cases) - Megakaryocytes produce excess platelet-derived growth factor (PDGF) >> marrow fibrosis - Hepatosplenomegaly - Tear-drop RBCS - Increased LDH and anemia

Primary myelofibrosis

- Neoplastic proliferation of mature myeloid cells, especially platelets - Symptoms related to an increased risk of bleeding and/or thrombosis (thrombocytosis > 450X) - Packed marrow with megakaryocytes

Essential thrombocythemia

- Rare dz, derived from histiocytic or dendritic cells - Histiocytic sarcoma - Tumors arising from LAngerhans cells - Interdigitating dendritic cell sarcoma - Disseminated juvenile xanthogranuloma

Mast / dendritic cell dz

- A clonal hematopoietic stem cell dz characterized by cytopenias and dysplasia in one or more major myeloid cell lines - Ineffective hematopoiesis - Increased risk for developing leukemia - Key feature = dysplasia *** - Increased apoptosis - Ringed sideroblasts seen in some forms - Usually older pts

Myelodysplastic syndrome

- T-cell lymphoma that strongly and uniformly expresses CD30 *** - 2 major types based on expression of ALK protein - Represents about 2% of adult non-Hodgkin lymphomas and 20-30% in children - Can be nodal or extranodal

Anaplastic large cell lymphoma

- Neoplastic accumulation of precursor B-cells (B lymphoblasts) in BM - MC type of ALL - Characterized by lymphoblasts (TdT+) - Always involves BM - Lymphoblasts = PAS+, MPO– (not myeloid) - CD10, CD19, CD79a, TdT+

B-cell acute lymphocytic leukemia | B-ALL

- Neoplastic accumulation of precursor T-cells (T lymphoblasts) in BM - Always involves BM - Lymphoblasts = PAS+, MPO - CD1a, CD3c, CD7

T-cell acute lymphocytic leukemia | T-ALL

- Neoplasm composed of mature B-cells characterized by hairy cytoplasmic processes - (+) for tartrate-resistant acid phosphatase stain (TRAP+) *** - Hepatosplenomegaly * - "Dry tap" on BM aspiration * - BRAF - CD11c, CD20, CD25, CD103, CD123

Hairy cell leukemia

- Neoplastic proliferation of mature CD4+ T-cells that infiltrate the skin, producing localized skin rash, plaques, and nodules - Aggregates of neoplastic cells in the epidermis are called Pautrier microabscesses - Cells can spread to involve the blood, producing Sezary syndrome - CD2, CD3, CD4, CD5, CD8, TCRß - T-cell genes are rearranged *

Mycosis fungoides

Triad: - Erythroderma - Generalized LAD - Circulating clonal T-cells with cerebriform nuclei *** - Thought of as end-stage mycosis fungoides

Sezary syndrome

Primary effusion lymphoma. Think...

Kaposi's

Pathology Flashcards

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