Pathoma-Lecture-Notes

Pathoma Lecture Notes

Chapter 1: Growth Adaptations,
Cellular Injury, and Cell Death

1.1 Growth adaptations

Hyperplasia Metaplasia Dysplasia

- Increase in cell number - Change in cell type due to - Proliferation of pre-
reprogramming of stem cell cancerous cells

- Reversible - Reversible - Reversible

- Pathologic hyperplasia - Can progress to dysplasia - Can progress to cancer
can progress to cancer and cancer

- BPH don't increase risk - Apocrine metaplasia don't

of cancer increase risk of breast cancer

- Etiology: - Etiology: - Etiology:

• Physiologic (ex- • Vit A deficiency • Long standing

pregnancy) (keratomalacia, pathologic hyperplasia

• Pathologic (ex - …) myositis ossificans) or metaplaisa

• Cellular stress (barret's

esophagus)

Processes Properties
Hyperplasia
and • Usually, hyperplasia and hypertrophy occur together
Hypertrophy • Permanent cell undergro hypertrophy only – cardiac myocytes, skeletal

Atrophy cells, and nerves.
• Pathologic hyperplasia (not physiologic ex- pregnancy) can progress to
Metaplasia
dysplasia and cancer.
• Exception is benign prostatic hyperplasia (is pathologic but does not

increase risk of cancer).

• can occur by decrease in cell number (apoptosis) or decrease in cell size.
• Decrease in cell size occurs by – ubiquitin-proteosome degradation of

cytoskeleton and autophagy of cellular components

• change in cell type.
• Mostly affects surface epithelium. Ex – barret’s esophagus (change from

squamous to columnar)
• MOA: occurs by reporgramming of stem cells
• Reversible
• Can progress to dysplasia and cancer. Ex – Barret’s. Exception –

Apocrine metaplasia doesn’t increase risk of breast cancer. Apocrine
metaplasia seen when fibrocystic changes in breast occur.
• Vitamin A deficiency can result in metaplasia. Ex – keratomalacia and
myositis ossificans.
• Mesenchymal tissue can undergo metaplasia (ex – bone, blood vessel,
fat etc). ex – myositis ossificans – inflammation of skeletal muscle reads
to metaplasia to bony tissue.

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Dysplasia Fig – myositis ossificans

• disordered cell growth; proliferation of precancerous cells. Ex - Cervical
intraepithelial neoplasia

• Arises from longstanding pathologic hyperplasia or metaplasia
• Reversible
• If dysplasia persists, it can progress to cancer.

Aplasia • Failure of cell production during embryogenesis. Ex – unilateral renal
Hypoplasia agenesis (failure to make 1 kidney)

• decrease in cell production in embryogenesis. Results in relatively small
organ. Ex – streak ovary in Turner syndrome.

Extras – Vitamin A is necessary for maturation of immune system. 15-17 translocation in
pt genome causes acute promyelocytic leukemia. The translocation causes mutation in vit-
A receptor – retinoic acid receptor. Mutation of receptors cause immune cells to be
trapped in blast stage. Treatment for Promyelocytic leukemia is all trans retinoic acid
(drug) which can bind to mutated receptor. Cells can mature and be neutrophil.

• Vitamin A is necessary for maintainence of special epithelial tissue in body – ex –
conjucitva of eye. Conjuctiva is a thin delicate membrane that covers eye. Deficiency
of vit A can result in metaplasia of cells in conjucitva where cells thicken which is
called keratomalacia.

• Fig – keratomalacia.

Cellular injury Page 1.2

1.2 Cellular injury

1. What is cellular injury?
- If cellular stress overcomes cell's ability to adapt, then cell gets injured.

2. What does cellular injury depend on?
- Type of stress
- Severity
- Type of cell - neurons can withstand hypoxia only for 3-5mins. Skeletal muscle can withstand for a

very long time.

3. What are causes of hypoxia(low O2 delivery to tissue)?
- ischemia,
- hypoxemia (PaO2<60 mm Hg),
- low O2 carrying capacity (ex - anaemia, CO poisoning, methmeglobinemia)

4. What is shock? What are it's causes?
- Shock is a generalized decreased perfusion of a vital organ. Can occur by hypovolemia,

cardiogenic, spetic, neurogenic, anaphylactic causes

5. What is Budd chiari syndrome?
- Blockade of hepatic vein can result in hepatic infraction, aka budd chiari syndrome.
- Most common cause of budd chiari syndrome is polycythemia vera. Polycythemia vera is a disease

with too much RBC which leads to clot formation. Another cause is lupus.

6. What will PaO2 and O2 sat be in anaemia?
- PaO2 and O2 sat will be normal in anaemia

7. What will PaO2 and O2 sat be in CO poisoning?
- PaO2 will be the same and O2 sat will reduce. CO binds to Hb 100 times stronger than O2.

8. What are signs/symptoms of CO poisoning?
- Early sign is headache (ask a pt if he has headache if you suspect CO poisoning). Pt may have

cherry red color skin.

9. What is methemoglobinemia?
- Normally, Fe in hemoglobin is in 2+ state and can bind to O2. If it gets oxidized to 3+, it can't bind

to O2 and this is methemoglobinemia.

10. What will PaO2 and O2 sat be in methemoglobinemia?
- PaO2 will be the same and O2 sat will reduce.

11. What are causes of methemoglobinemia?
- Oxidative stress - sulfa drugs, nitrate drugs. Also seen in newborns because their machinery to
reduce Fe 3+ isn't good.

12. What are signs/symptoms of methemoglobinemia?
- Cyanosis with chocolate colored blood.

13. What is treatment of methemoglobinemia?

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13. What is treatment of methemoglobinemia?
- IV methylene blue - it generates moderators that will reduce Fe3+

14. What are consequences of low ATP in cell?
- Lactic acidosis due to lots of glycolysis
- Disrupted Na/K pump result in Na accumulation and resulting water retention in cell
- Disrupted Ca pump result in Ca accumulation and random enzyme activation in cytosol

15. What are reversible finding in cell of low ATP?
- Hallmark is cellular swelling - loss of microvilli, membrane blebing as it pulls away from the
cytoskeleton, swelling of RER and ribosomes fall off (low protein synthesis)

16. What are irreversible finding in cell of low ATP?
- Hallmark is membrane damage. End result is cell death.
- Cellular enzymes leak out (liver enzyme in hepatitis and cardiac enzyme in MI) and intracellular Ca
increases.
- Cytochrome C from mitochondria leaks out to cytosol and activates apoptosis
- Lysozome enzymes will leak out and digest the cells. Ca in cytosol activates them.

Cellular injury Page 2.2

1.3 Cell death

1. What is morphologic hallmark of cell death?
- Loss of nucleus
2. What are the steps by which nucleus is lost?
• Pyknosis - shrinking of nucleus
• Karyorrhexis - breaking of nucleus to big pieces
• Karyolysis - big nuclear pieces broken down to molecular building blocks

3. Explain necrosis
• Necrosis occurs as a result of acute inflammation to a large group of cells and is always pathologic
• Types

1. Coagulative necrosis
2. Liquefactive necrosis
3. Gangrenous necrosis - dry and wet
4. Caseous necrosis
5. Fat necrosis
6. Fibrinoid necrosis
4. Describe coagulative necrosis
- Cell and organ structure is preserved by coagulation of cellular proteins
- Characteristic of ischemic infarction of any organ except brain

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Fig - right is normal glomerulus and left is coagulative necrosis of glomerulus. Note cellular
and organization structure is preserved with loss of nucleus.
- Area of infracted tissue is often wedge shaped and pale. Wedge points to the blocked blood
vessel.
5. When does red infraction (hemorrhagic infraction) occur?
• Red infraction occurs when blood reenters a loosely organized tissue. Ex - ischemia of testis, lungs.
(is red infraction a type of coagulative necrosis?)
6. Describe liquefactive necrosis
- Necrosis in which enzymatic lysis of cells and proteins result in liquefaction
- Characteristic of brain (microglial cells destroy the tissue), abscess (neutrophils contain hydrolytic
enzyme that destroy the tissue), and pancreatitis (pancreatic enzyme digest the pancreas and
liquify; however surrounding fat will have fat necrosis)
7. Describe gangrenous necrosis
- It is coagulative necrosis that resembles mummified tissue (dry gangrene). If infection occurs on
dry gangrene, liquifactive necrosis occurs and is called wet gangrene.
- Characterstic of ischemia of lower limb and GI tract
8. Describe caseous necrosis
- It is soft, friable necrosis with 'cottage cheese' like appearance
- It's liquefactive necrosis with debris that thickens the soup to make it cheese like
- Characteristic of granulomatous inflammation of TB or fungal infection (fungal cell wall and
micobacterium thickens the soup).

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Fig - caseous necrosis

9. Describe fat necrosis
- Necrotic fat with Chalky white appearance due to deposition of Ca. MOA - When fat cells die by

trauma or when fat is broken down by lipase, fatty acids are released. In presence of Ca,
saponification occurs which gives it the chalky white apperance. Ca accumulation happens by
dystropic calcification.
- Characteristic cases - trauma to fat (ex - as in car accident trauma in breast), pancreatitis mediated
damage of peripancreatic fat

Fig - fat necrosis around pancreas

10. What is fibrinoid necrosis
- Necrotic damage to blood vessel
- Proteins leak into vessel wall which results in bright pink staining of vessel wall in H&E
- Characteristic of malignant hypertension and vasculitis. Pre-eclampsia can cause fibrinoid necrosis
of placenta. (benign HTN is chronic low increase in BP that cause slow damage. Malignant
hypertension is sudden super elevated BP that is a medical emergency - findings such as
headache, renal failure, papilledema). Super high BP in malignant HTN can kill vessel wall cells.

11. What are mechanism by which calcium can deposit in human tissue?
- Dystropic calcification
- Metastatic calcification

12. What is dystropic calcification?
- It's a mechanism by which Ca deposits in a human body (it's abnormal as calcium is not supposed
to just randomly accumulate). Mechanism - when there's a dead tissue, calcium can accumulate
even if serum Ca is normal. Ex - in fat necrosis, in tumor as center of tumor might not get enough
blood supply and die.

13. What is metastatic calcification?

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13. What is metastatic calcification?
- Serum Ca or PO4 is elevated. This elevated stuff can force Ca to accumulate on tissue. It doesn't
mean that pt has metastatic cancer.

Apoptosis
14. Explain apoptosis. (apoptosis means falling of leaves)

- It is purposeful, energy dependent killing of small group of cells
- Examples - Endometrial shredding during menstruation, removal of cells in embryogenesis, CD8

cell mediated killing of virally infected cells

15. What is mechanism of apoptosis?
- Cell shrinks (and becomes eosinophilic due to concentration of cytoplasm) and nucleus also
shrinks and fragments.
- Apoptotic bodies fall from cell like leaves fall from tree. Then they are eaten by macrophage. No
inflammation occurs

Fig - compare the pink apoptotic cell to it's surrounding neighbors

16. What is biochemical pathway leading to apoptosis?
- Caspase activation is the key step.
○ Caspases activate proteases that break down cytoskeleton.
○ Caspases also activate endonucleases that break down nucleus.

17. What 3 pathways lead to caspase activation? (HY)
- Intrinsic mitochondrial pathway - Bcl2 is a protein whose function is to stabilize mitochondrial
membrane so that cytochrome C from mitochondria can't leak out. Due to membrane damage
(cellular injury), DNA damage, or decreased hormonal stimulation of cell (ex - endometrial cells in
lack of estrogen), Bcl2 can be inactivated. Leakage of cytochrome C will then activate caspase.
- Extrinsic receptor-ligand pathway -
○ Example- FAS ligand binds to FAS death receptor (CD95) on target cell and target cell dies
via activation of caspases. Case report - new CD8+ T cells from bone marrow undergo
positive selection (I.e., if they can bind to self antigen on MHC-I molecule, they get to live)
and negative selection (i.e., if they bind to self antigen on MHC-I molecule very strongly,
they die) in thymus. The killing of these young T-cells in negative selection happens by
binding of FAS ligand to FAS death receptor on T-cells.
○ Another example - TNF binds to TNF receptor on target cell and cell dies.
- Cytotoxic CD8+ T-cell pathway - When CD8+ cells recognize foreign antigen on MHC-I receptors,
they release perforins that make holes on target cell. Then, they release granzyme that enter
target cell and activate caspases.

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1.4 Free radical injury (HY)

1. What is free radical?
• Atoms or molecules with unpaired electron in outer orbit

2. Give example of physiologic and pathologic free radical?
• Physiologic - in oxidative phosphorylation, when oxygen receives 1, 2 or 3 electron, it's partially

reduced and creates superoxide (O2.), hydrogen peroxide (H2O2), and hydroxide(.OH) free radical
respectively. Only if O2 receives 4 electron, it becomes water. Of all free radicals, hydroxide free
radical is most damaging (HY).

Oxygen ----(accept 1 electron)-----> Superoxide (.O2) ----(accept 1 electron)-----> Hydrogen
peroxide (H2O2) ----(accept 1 electron)-----> Hydroxide (.OH) ----(accept 1 electron)-----> Water
(H2O)

• Pathologic -
▪ ionizing radiation (creates hydroxide radical .OH),
▪ inflammation (in neutrophils, O2 is converted to superoxide by NADPH oxidase)
▪ Metals - iron and copper. Hemochromatosis and Wilson disease are disease of Fe and
Cu accumulation in body - creation of free radicals are main way that the disease
affect us. (Fenten reaction - reaction by which Fe generates hydroxide free radical
(HY))
▪ Drugs and chemicals - acetaminophen, carbon tetrachloride. High dose of
acetaminophen causes liver necrosis by free radical generation
▪ Thyroid hormones increase free radical formation

3. How do free radicals harm the cell?
• Oxidation of DNA (lead to fast aging and cancer) and oxidation of proteins
• Peroxidation of lipids

4. What are 3 mechanism of removal of free radicals? Give example of 3 enzymes.
• Antioxidants - vit K
• Metal carrier proteins - transferrin, ferretin
• Enzymes (HY)

○ Superoxide dismutase (gets rid of superoxide)
○ Catalase ( gets rid of hydrogen peroxide)
○ Glutathione peroxidase (get rid of hydroxide free radical)

5. Give example of 2 free radical injury? (HY)
• Carbon tetrachloride (dry cleaning chemical)- CCl4 is converted to CCl3 (radical) by Cyp 450 in

liver. It causes reversible damage to hepatocytes - cell swells --> swelling of RER causes ribosomes
to fall off and apolipoprotein synthesis goes down --> liver can't repackage and send fat away -->
fatty liver disease (VHY)

Cellular injury Page 4.1

Fig - T represents fat in hepatocyte; a hepatocyte is shown in circle
• Reperfusion injury - During reperfusion of ischemic organ, immune cells will attack the dead tissue

in presence of oxygen which will generate free radicals. More injury ensues. Classic example is
blood troponin continuing to rise after reperfusion of heart after MI.

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1.5 Amyloidosis

1. What is amyloid?
• Misfolded proteins that accumulates in extracellular space and damages tissue. Amyloid can't be

removed and damaged organs must be transplanted

2. What are characters of amyloid?
• Misfolded proteins have B-sheet arrangement
• Amyloid are congo red positive (appear apple-green under polarized light)

Fig - apple-green appearing amyloid under polarized light
• Amyloid can be deposited systemically or locally

3. What are 2 types of systemic amyloidosis?
• Primary amyloidosis - When Ig light chain deposits systemically (in form of AL amyloid), it's called

primary amyloidosis. It's associated with plasma cell dyscrasias (disease) - when plasma cells make
ton of light chain, they will deposit.
• Secondary amyloidosis - when SAA protein deposits systemically (in from of AA amyloid), it's called
2ndary amyloidosis. SAA is acute phase reactant that is increased in chronic inflammatory states,
malignancy, and Familial Mediterranean fever.

4. What is familial mediterranean fever (HY)?
• It's genetic disease with dysfunction of neutrophils that causes systemic amyloidosis. It's usually

seen in people of mediterranean origin.
• Pt will have high SAA that deposits at AA amyloid
• Pt may present with acute fever and serosal inflammation (serosal inflammation of heart might

mimic MI, of gut may mimic appendicitis)

5. What are classic findings of systemic amyloidosis?
• Kidney is most commonly involved - nephrotic syndrome is seen
• Restrictive cardiomyopathy or arrhythmia
• Hepatosplenomegaly, malabsorption, large tongue

6. How do you diagnose amyloidosis?
• Requires tissue biopsy (needs to be congo-red positive) - usually take from rectum or abdominal

fat pads

7. Describe senile cardiac amyloidosis (a type of local amyloidosis).
• Caused due to deposition of non-mutated serum transthyretin in heart. Transthyretin is 2nd most

common protein in blood.

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common protein in blood.
• Usually asymptomatic and seen in 25% of people >80 year
8. Describe familial amyloid cardiomyopathy (a type of local amyloidosis).
• Caused due to deposition of mutated serum transthyretin in heart.
• Leads to restrictive cardiomyopathy
• Usually seen in african americans (5% carry mutation)
9. Describe how type 2 diabetes has local amyloidosis in it.
• Due to insulin resistance, pancreas produces lots of insulin. A byproduct amylin is also produced

that deposits in islets of pancreas and cause amyloidosis.
10. Describe how alzhimer's has local amyloidosis in it.

• B-amyloid precursor protein (BAPP) on chromosome 21 makes AB amyloid plaques. (Most
individuals with Down's syndrome have Alzheimer's by 40 year age)

11. Describe how dialysis can cause local amyloidosis in joints.
• Beta2 microglobulin is a protein that structurally supports MHC-I on cell surface. In dialysis, B2-
microglobulin isn't filtered well from blood. It then builds up in joints and cause amyloidosis.

12. Describe how medullary thyroid cancer can cause local amyloidosis in thyroid.
• In MTC, overproduction of calcitonin leads to formation of calcitonin amyloid plaques in thyroid.
(In FNA of thyroid, seeing tumor cells in amyloid background makes MTC more probable)

Cellular injury Page 5.2

Chapter 2: Inflammation,
Inflammatory Disorders, and Wound

Healing

2.1 Acute Inflammation (Part 1)

1. What is inflammation?
• Process by which inflammatory cells, plasma proteins and fluid exit blood vessel to enter
interstitial space

2. Explain acute inflammation
- Characterized by edema and neutrophil in tissue (presence of neutrophils define acute
inflammation)
- Arises in response to infection or necrosis (necrosis is always followed by acute inflammation (HY))
- Goal is to clear pathogen or necrotic debris
- Part of innate immunity (very quick response)

3. How does TLR work?
- Toll like receptors (TLR)- present on cells of innate immune system (macrophage, dendritic cells)
and adaptive immune system. In innate system, TLR recognize PAMP (pathogen associated
molecular patterns)and DAMP (damage associated molecular pattern). Ex - CD14 (aka TLR-4) is a
TLR on macrophage that recognizes lipopolysaccharide (LPS) which is shared by gram negative
bacteria. (HY)

3.1 What chemical is upregulated by TLR?
- NF-KB- NF-KB is a molecular switch that turns on acute inflammation (master regulator for both
innate and adaptive immunity).
- Type 1 interferon (alpha and beta) - inhibit viral replication in cells

Arachidonic acid metabolism
4. Explain production and metabolism of arachidonic acid (AA).
- Phospholipase A2 releases AA from phospholipid cell.
- AA can then be metabolized by cyclooxygenase or 5-lipooxygenase.

5. What are the products of cyclooxygenase pathway and what are their functions.
- Cyclooxygenase pathway produces prostaglandins (PG) - PGI2, PGD2 and PGE2. They increase

vascular permeability and vasodilation. PGE2 also mediates feeeever and pain. Note that
vasodilation happens at arteriole level and vascular permeability at post capillary venule level.

6. What are the products of lipooxygenase pathway and what are their functions
- 5-Lipooxygenase pathway produces leukotrienes (LT). LTB4 attracts and activates neutrophils.

LTC4, LTD4 and LTE4 mediate smooth muscle contraction (vasoconstriction, bronchospasm, and
increased vascular permeability (contraction of pericytes opens up space between endothelial
cells)).

7. What are 4 important things that attract and activate neutrophils?
- LTB4 (leukotriene)
- C5A (complement protein)
- IL8 (mechanism by which macrophage call neutrophil)
- Bacterial products
- TNF and IL1 (based on Abbas book)

Mast cells
7. What are 3 ways that activate mast cells?
- Mast cells are found throughout connective tissue of body and are activated by -

Inflammation Page 1.1

- Mast cells are found throughout connective tissue of body and are activated by -
○ Tissue trauma
○ Complement proteins C3a and C5a
○ Cross linking of cell surface IgE by antigen (2 or more IgE on a mast cell binds same antigen)

8. What is acute response of mast cells activation?
- Histamine is released which causes vasodilation and increased vascular permeability.
- Release proteolytic enzymes that kill bacteria or inactivate toxins

9. What is delayed response (after 4-5 hrs) of mast cells activation?
- Mast cells produces arachidonic acid metabolites, particularly leukotrienes. (HY)

Complement
10. What are three pathways of complement activation?

- Classic pathway - C1 protein binds to IgG or IgM which is bound to antigen (pneumonic - GM
makes classic cars)

- Alternative pathway - microbial products directly activate complement
- Mannose binding lectin (MBL) pathway - MBL binds to mannose on microorganisms and activate

complement

11. How is membrane attack complex (MAC) formed?
- C3 convertase converts C3 to C3a and C3b
- C5 convertase converts C5 to C5a and C5b
- C5b joins with C6 and C9 to make membrane attack complex (MAC) which pokes hole in cell and
kill it.

12. What are some key functions of complement proteins? (HY)
- C3a and C5a activate mast cells (stimulate degranulation)
- C5a is chemotactic for neutrophil
- C3b is opsonin for phagocytosis. Opsonins tag cells/waste for phagocytosis.
- MAC pokes hole in cell and kill it

13. What is hageman factor (aka factor 12 in coagulation cascade)? What systems does it activate?
- It's inactive proinflammatory protein produced in liver that's activated by exposure to
subendothelial or tissue collagen, and during severe gram negative sepsis
- Plays imp role in DIC (disseminated intravascular coagulation - pathologic activation of coagulation
cascade) and severe gram negative sepsis (sepsis activates hageman factor which in turn results in
DIC) (HY).
- It activates complement system, coagulation and fibrinolytic system (this results in DIC), and kinin
system

13.1. Explain kinin system.
- Kinin system cleaves high molecular weight kinin to bradykinin. Bradykinin results in vasodilation,
increased vascular permeability and pain). Note - bradykinin system has histamine + pain functions

14. What two molecules mediate pain?
- Prostaglandin E2 (cause feeever and pain)
- Bradykinin

Cardinal signs of inflammation - rubor, calor
15. What causes rubor (redness) and calor (warmth)?

- Vasodialation due to arteriole relaxation mediated by - histamine (primary), bradykinin and PG.

16. What causes tumor (swelling)?

Inflammation Page 1.2

16. What causes tumor (swelling)?
- Increased vascular permeability at post capillary venule mediated by - histamine, bradykinin,
lukotrienes, PG, and tissue damage.

17. What causes dolor (pain)?
- Bradykinin and PGE2.

18. What causes fever? (VHY)
- Macrophage release IL-1 and TNF. They go to perivascular cells of hypothalamus and increase
activity of COX. (inflammosome also makes IL1)
- COX causes increase in PGE2 in hypothalamus which increases temp set point.

Inflammation Page 1.3

2.1 Acute Inflammation (Part 2)

1. What are 3 phases of acute inflammation?
○ Fluid phase - edema, complement activation etc
○ Neutrophil phase - peaks about 24 hrs
○ Macorphage phase - peaks about 2-3 days
(Note that acute inflammation is not defined by time. It can happen for days or weeks. It
is defined by whether neutorphils are primary player. If pus is present, it's still acute.)

2. What are steps of neutorphil exit? What proteins are key in each step?
- Margination - Usually, heavy particles in blood are in center of vessel lumen. When blood

vessel dilates, heavy particles come to edge of vessel and this is margination. It's first step of
neutrophil arrival.
- Rolling - endothelial cells express proteins called selectins which act as speed bump so that
neutrophils roll and slow down.
- Adhesion - cellular adhesion molecules (CAM) on endothelium binds to integrins on
neutrophil resulting in adhesion. (HY)
- Transmigration and chemotaxis - transmigration happens across vessel wall of postcapillary
venules, and chemotaxis is movement to infection site after transmigration. Neutrophils are
attracted by bacterial products, IL8, C5a and LTB4
- Phagocytosis - enhanced by opsonins (IgG and C3b)

3. What induces P selectin and E selectin?
- P selectin release is induced by histamine. They are released from Weibel-Palade bodies in

endothelial cells (another stuff made by weibel-palade body is Von-willieband factor).
- E selectin release is induced by TNF and IL-1.

4. What protein on neutrophils does selectins bind to?
- Sialyl Lewis X. It results in rolling .

5. What upregulates cellular adhesion molecules (CAM) on endothelium?
- IL1 and TNF

5.5. What are major innate immunity cytokines?
- IL-1 and TNF

6. What upregulates integrins on neutrophils?
- C5a and LTB4 (recall that C5a and LTB4 are 2 of the 4 things that attract and activate

neutorphils - other 2 being bacterial product and IL8)

7. What is leukocyte adhesion deficiency? Where is the mutation?
- It's autosomal recessive mutation of integrins at CD18 subunit.

8. What are sign/symptoms of leukocyte adhesion deficiency (LAD)? (HY)
- Delayed seperation of umbilical cord (HY) - After childbirth, the umbilical cord shuts. Due to

no blood through it, it undergoes necrosis. Active inflammation ensues. Neutrophils come and
eat up umbilical cord. However, in LAD, neutrophils won't come much because adhesion
process is bad.
- Increased circulating neutrophils (HY) - normally, half of neutrophils are in circulation and
remaining half are stuck to endothelium of lung. Due to loss of adhesion, circulating

Inflammation Page 2.1

remaining half are stuck to endothelium of lung. Due to loss of adhesion, circulating
neutrophils will increase.
- Recurrent bacterial infection but lack pus formation (HY) - Pus is dead neutorphil in fluid. If
neutrophils can't get into tissue, pus can't form.
9. Where do neutrophils exit blood vessel?
- Post capillary venule.
10. How does phagocytosis occur?
- Neutrophils engulf stuff and make phagosome. Phagosome merges with lysosome to make
phagolysososme. (C3b and IgG are major opsonins)
11. What is Chediak-Higashi syndrome?
- It's an autosomal recessive protein trafficking defect (microtubule railroad tracks in the cells
are defective).
12. What are sign/symptoms of Chediak-Higashi syndrome? (HY)
- It's symptoms are based on impaired microtubule railroad tracks

○ Immune fingings-
 Neutropenia (impaired cell division so low neutrophils)
 Giant granules in leukocytes (newly made granules from golgi won't travel well to
other parts of cell and pile up)
 Increased pyogenic infections (phagosome merging with lysosome is impaired, so
immune cells are less efficient at killing pathogens).

○ Defective primary hemostasis (granules in platelets won't move well)
○ Albinism (a melanocyte supplies melanin to about 25 keratinocytes. As railroad

transport is defective, it's melanin won't be transported to other keratinocytes)
○ Peripheral neuropathy - stuff from cell body of neuron won't be transported to axon

endings well.

Inflammation Page 2.2

2.1 Acute Inflammation (Part 3)

1. What are two mechanism of phagocytosis? Which is more efficient
• Oxygen dependent and oxygen independent.
• Oxygen dependent is more efficient

2. Explain O2 dependent mechanism of phagocytosis. (HY)
• It occurs in phagolysosome
• Oxygen is converted to superoxide (radical) by NADPH oxidase (rxn called oxidative burst).
• Superoxide is coverted to hydrogen peroxide by superoxide dismutase.
• Hyrodgen peroxide is converted to bleach (HOCl) by myloperoxide (MPO)
• HOCl kills organism

3. What is mechanism of Chronic granulomatous disease (CGD)?
• Due to defect in NADPH oxidase, O2 dependent phagocytosis is bad and patient has chronic
granulomas. Disease is autosomal recessive or X-linked.
• As pt can't phagocytose, more and more macrophage and neutrophils are called to site resulting in
formation of granulomas.

4. What are 5 catalase positive organism that cause symptomatic CGD? (HY)
○ S Aureus
○ P cepacia (often tested)
○ S marcescens
○ Nocardia
○ Aspergillus

5. Why do only catalase positive organism cause CGD?
• Most bacterias produce H2O2 which can be converted to bleach by myloperoxidase in body.
Therefore, most bacteria can't cause CGD despite mutation in human NADPH oxidase. However,
when bacteria have catalase, that destroys H2O2 and formation of bleach is reduced which results
in CGD.

Inflammation Page 3.1

in CGD.

6. What is nitroblue tetrazolium (NBT) test?
• It's a screening test for CGD. In the test, solution turns blue if superoxide radical is present. It tests
if NADPH oxidase is functional.

7. What is clinical significance and NBT test result for people with myloperoxide (MPO) deficiency?
• Most MPO patients are asymptomatic but have increased risk for candida infection.
• They have normal NBT test.

8. Explain oxygen independent phagocytosis.
• It's less effective and occurs via enzyme in secondary granules (ex - lsyozome and major basic
protein).

9. Describe the resolution phase of acute inflammation.
• Within 24 hours of resolution of inflammatory stimulus, neutrophils die by apoptosis. It creates
pus. Pus is dead neutrophils in fluid.

10. Describe macrophage phase of acute inflammation.
• It peaks 2-3 days after inflammation begins.
• When monocytes get into tissue, they are called macrophage. They come to tissue in same steps
as neutrophils.

11. Contrast phagocytosis of macrophage with that of neutrophil.
• Phagocytotic killing of macrophage is mainly oxygen independent - via the enzymes in secondary
granules. Lysozyme is main enzyme.
• Phagocytotic killing of neutrophil is mainly oxygen dependent.

12. What happens after fluid, neutrophil and macrophage phase of acute inflammation? (HY)
• Macrophage are managers which come in to check after 2-3 days of acute inflammation if
neutrophils did a good job at clearing the damage.
• If good job is done, macrophage secrete IL-10 and TGF-B. They are anti-inflammatory and induce
healing.
• If job is done poorly, macrophage secrete IL-8. It calls additional neutrophils to the site.
• If macrophage sense that the offending organism needs to walled off, they create abscess.
Abscess is walled off area of inflammation.
• If macrophage sense that neutrophils can't do the job well (ex- neutrophils don't work well in viral
injury), they initiate chronic inflammation by presenting antigen in MHC-2.

Inflammation Page 3.2

2.2 Chronic inflammation

1. What is chronic inflammation?
• Inflammation is bringing out immune cells into the tissue. In chronic inflammation, mainly
lymphocytes are brought out. In acute inflammation, mainly neutrophils are brought out.
• It's delayed response (adaptive immunity) and more specific.

Fig - chronic inflammation. Note the absence of multilobed neutrophil. Cell on left is lymphocyte.
Middle cell is plasma cell (nucleus pushed to side, slight perinuclear halo). Cell on right is
macrophage (clock face nucleus).

2. What are stimuli of chronic inflammation?
• Persistent infection (most common)
• Infection with virus, mycobacteria, parasites, fungi
• Autoimmune disease
• Foreign material
• Some cancers

T cells
3. Explain development and maturation of T-cells.

• They are made in bone marrow and go to thymus.
• In thymus, they become specific to an antigen and develop into either to CD4 helper or CD8

cytotoxic cell.

4. How are CD4 and CD8 T-cells activated? What is their second message for activation?
• T cells are activated when they recognize antigens presented on MHC molecules only while a
second signal is present.
• Helper CD4 T cells read antigen from MHC II. MHC II present extracellular antigen and are present
on antigen present cell.
• Cytotoxic CD8 T cells read antigen form MHC I. MHC I present intracellular or viral antigen and are
present on all cells in body
• For CD4 cells, B7 on antigen presenting cell is the second signal that binds to CD28 on CD4 cells.
CD40 on B cells also act as second signal that bind to CD40L on CD4 cells.
• For CD8 cells, IL2 from CD4 cells is second signal for activation.

5. What do activated CD4 cells do?
• Activated CD4 helper cells secrete cytokines. They have two subtypes - TH1 and TH2.

6. Explain purpose and function of cytokines secreted by activated CD4 TH1 cells.
• TH1 secrete IFN gamma that enhances phagocytic ability of macrophage
• TH1 also secrete IL2 which is T cell growth factor and CD8 cells activator

7. Explain purpose and function of cytokines secreted by activated CD4 TH2 cells.
• TH2 cause eosinophil rich inflammation and/or reduce inflammation by secreting IL4, IL5 and IL10.

Inflammation Page 4.1

• TH2 cause eosinophil rich inflammation and/or reduce inflammation by secreting IL4, IL5 and IL10.
• IL 4 cause class switching to IgG and IgE
• IL5 attracts and activates eosionophil, helps in maturation of B cells to plasma cells and cause class

switching to IgA
• Il10 (antiinflammatory cytokine) inhibits TH1 phenotype.

8. How do CD8 T cells kill cells?
• They secrete perforins that make holes in host cell and secrete granzymes that activate caspase
and induce apoptosis.
• They express Fas ligand which binds to Fas receptor on host cell that activates apoptosis.

8.1. How is a self-reactive T-cell killed?
- If there's a self-reactive T-cell, it will bind to MHC-antigen but the second signal won't be present.
It will result in apoptosis or anergy.

B cells
9. How are B cells produced?

• Immature B cells are produced in bone marrow. Naïve B cells express IgM and IgD.

10. How are 2 ways by which B cells activated? How does isotype switching occur?
• Binding of antigen to IgM or IgD activates B cells. Then they become IgM or IgD secreting plasma
cells.
• B cells can phagocytose and present antigen to CD4 cells via MHC II. CD40 on B cell can bind to
CD40L on helper T cell providing 2nd signal for activation.
• TH2 Helper T cell will secrete IL4 and IL5. IL4 and IL5 help in isotype switching of B cells, somatic
hypermutation (aka affinity maturation), and maturation to plasma cells.

Granulomatous inflammation
11. What is granulomatous inflammation?

• It’s a type of chronic inflammation. It's defined by presence of epitheloid histiocytes (macrophage
with abundant pink cytoplasm and elongated nuclei) (HY). You may also see multinucleated
macrophages. In healthy tissue, macrophage have clear (aka foamy) cytoplasm.

• Granulomas are surrounded by rim of lymphocytes and giant cells.
• Only a certain conditions give granuloma so they help to identify diseases.

12. What cause noncaseating granulomas?
• Defining feature of noncaseating granuloma is lack of central necrosis.
• Causes:
○ Reaction to foreign material - ex- leaking of breast implants
○ Sarcoidosis - hallmark of sarcoidosis is production of non-caseating granuloma in multiple
organs (mainly lungs)
○ Beryllium exposure
○ Crohn disease - hallmark of Crohn is noncaseating granuloma. (hallmark of UC is crypt
abscess)
○ Cat scratch disease - give star shaped granuloma in neck

Inflammation Page 4.2

Fig - noncaseating granuloma. Not abundant lymphocytes in periphery that indicates chronic
inflammation. Note multinucleated cell. Presence of nucleus in epitheloid histiocytes means
they are alive - making this noncaseating granuloma.
13. What causes caseating granuloma?
• Characteristic of TB and fungal infections. If you see caseating granuloma, do AFB stain to look for
TB, and GMS silver stain to look for fungal infections.

Fig - caseating granuloma. Note the central necrosis
14. How are granulomas formed? (HY)

• Macrophage present antigen to CD4 T cells via MHC II
• After binding, macrophage also secrete IL-12 that induce CD4 cells to differentiate to Th1 subtype
• Th1 cells secrete IFN gamma which converts macrophage to epitheloid histiocytes and giant cells.

Granuloma is hence formed.
• These steps occur in both caseating and non-caseating granuloma

Inflammation Page 4.3

2.3 Primary immunodeficiency

1. What is DiGeorge syndrome (HY)?
• Failure to develop 3rd and 4th pharyngeal pouch due to 22q11 mutation.

2. What are presentation of DiGeorge syndrome?
• T cell deficiency- problems fighting viral and fungal infection (due to lack of thymus as thymus develops from 3rd and
4th pouch)
• Hypocalcemia (due to lack of parathyroid)
• Abnormalities of heart, great vessels, and face

3. What is SCID (severe combined immune deficiency)?
• Pt have defective cell-mediated and humoral immunity (both T and B).

4. Etiology of SCID?
• Cytokine receptor defects (main cause)
• Adenosine deaminase deficiency (second main cause)(HY) - enzyme necessary for deamination of adenosine and
deoxyadenosine. In lack of enzyme, adenosine and deoxyadenosine accumulates in immune cells causing toxicity.
• MHC class II deficiency - CD4 won't be able to be activated. It leads to defective function of CD8 and B cells.

5. Presentations of SCID?
• Lack of T cells result in fungal and viral infections
• Lack of B cells result in bacterial and protozoal infections
• Increased opportunistic infection and be wary to give live vaccines.

6. Treatment of SCID?
• Sterile isolation (bubble babies)
• Stem cell transplant

8. What is X-linked agammaglobulinemia? What is the mutation?
• Name suggests pt lacks gammaglobulin (antibodies) in blood. There's a complete lack.
• Occurs because naïve B cells can't mature to plasma cells.
• Mutation is Bruton tyrosine kinase. It's a signaling receptor that helps maturation of B cells.

9. What is presentation of X-linked agammaglobulinemia?
• Recurrent bacterial, enterovirus, and Giardia infection (HY).
• Enterovirus affects mucosa of GI tract. IgA protects mucosal surface, and lack of IgA results in enterovirus infection.
• Bacterial infection occurs because lack of antibodies affect opsonization.
• Giardia occurs for same reasoning as enterovirus.
• Presents after 6 month of life – because mom's antibodies last for about 6 months
• Don't give them live polio vaccines

10. What is common variable immunodeficiency disease?
• Pt has low antibodies due to defective B or T cell

11. Presentation?
• Pt has increased risk of bacterial, enterovirus, giardia infection, often in late childhood.
• They have increased risk of autoimmune disease and lymphoma. (HY)

12. What is IgA deficiency?
• This is most common Ig deficiency. Pt have low serum and mucosal IgA which increases risk of mucosal infections –
especially viral.

Inflammation Page 5.1

especially viral.
Note – pt with celiac disease usually have IgA deficiency.
13. What is Hyper-IgM syndrome?
• Pt have too much IgM.
14. What is pathophysiology of Hyper-IgM syndrome? What is presentation?
• Patient has mutation in CD40 or CD40 receptor. Due to this, B cells can't activate CD4. In lack of good CD4, cytokines
necessary for Ig class switching is not produced. Pt will have low IgA, IgG, and IgE.
• Presentation is recurrent pyogenic infections, especially at mucosal sites. IgG is a opsonin, low amount results in more
formation of pus.
15. What is Wiskott-Aldrich syndrome (WAS)? What causes it? (just memorize)
• Pt have thrombocytopenia, eczema, and recurrent infections. Pt have defective humoral and cellular immunity.
• Happens due to mutation in WASP (Wiskott-Aldrich syndrome protein) gene and is x-linked.
16. What are the consequence of the following complement deficiencies? (just memorize)
• Deficiency from C5-C9 - increased risk of Neisseria infection (HY)
• C1 inhibitor deficiency - hereditary angioedema characterized by edema of skin (especially periorbital) and mucosal

Fig - heriditary angioedema.

Inflammation Page 5.2

2.4 Autoimmune Disorders

1. What causes autoimmune disorders?
- Overactive immune system or loss of self tolerance.

2. What is epidemiology of autoimmune disorders.
- Present in about 1% of US popn.
- Most affects women. Classically affects women of childbearing age.
- Most autoimmune diseases are associated with other autoimmune diseases.

3. What is etiology of autoimmune disorders?
- Environment triggers disease in genetically susceptible individuals.

Systemic Lupus
4. What happens in Lupus?
- Lupus is a systemic autoimmune disease in which autoantibodies can cause type II (cytotoxic -
antibody bind and kill cells) or type III hypersensitivity reaction (antigen-antibody complex form
and deposit in tissue causing damage).

5. What are clinical features of lupus?
- Malar 'butterfly rash' upon exposure to sunlight is classic sign
- Diffuse proliferative glomerulonephritis commonly occurs; other nephritic/nephrotic symptoms

can occur too. Renal damage is common cause of death
- Pleuritis and pericarditis, myocarditis, endocarditis
- Libman-Sacks endocarditis - vegetations on both side of valve
- Antibodies against blood result in - anemia, thrombocytopenia or leukopenia. Infections due to

loss of immune system also a common cause of death.
- CNS psychosis due to inflammation of CNS
- Fever and weight loss (fever is sign of inflammation)
- Arthritis

Fig - malar butterfly rash in lupus pt.

6. Describe Libman-Sacks endocarditis.
- Mostly, endocarditis happens only on one side of valve (up or down). If it happens on both side of

valve, it's called Libman-Sacks endocarditis and is characteristic of lupus.

7. How do we diagnose lupus?
- ANA (anti-nuclear antibody) very sensitive for lupus - used for screening
- Anti-dsDNA very specific for lupus

Inflammation Page 6.1

8. What are three common drug that cause lupus? How do we diagnose? How do we treat?
- Hydralizine, procainamide and isoniazid
- Antihistone antibodies are specific for drug induced lupus
- Removal of drug causes remission of disease

9. What is antiphospholipid syndrome associated with SLE? What lab tests does it affect?
- Antibodies are made against proteins bound to phospholipid.
- Anticardioliptin antibody give false positive syphilis test.
- Lupus anticoagulant antibodies give falsely elevated PTT lab study but makes pt hypercoagulable.

10. Why do you keep pt with antiphospholipid syndrome on lifelong anticoagulation?
- Because lupus anticoagulant antibodies make pt hypercoagulable and increase risk of stroke, DVT,
hepatic vein thrombosis, placental thrombosis (pregnancy loss).

Sjogren syndrome
11. What is sjogren syndrome?

- Type IV (lymphocyte mediated) autoimmune destruction of lacrimal and salivary glands with
resulting fibrosis.

12. What are clinical presentation of Sjogren syndrome?
- Dry eyes, dry mouth and recurrent dental carries (bacteria accumulates as teeth aren't washed) in
older woman.
- Parotids may be enlarged due to fibrosis.
- "Can't chew cracker, dirt in my eyes"

13. How do you diagnose Sjogren syndrome?
- Presence of ANA is sensitive
- Presence of anti-ribonucleoprotein antibodies is specific - (Anti SSA and anti SSB antibodies -
Sjogren syndrome A and sjogren syndrome B)

14. What other conditions is Sjogren syndrome associated with?
- Other autoimmune disorders - especially rheumatoid arthritis
- High risk for B-cell lymphoma (HY) - unilateral enlargement of partoid gland late in disease is
indicative of B-cell lymphoma.

Scleroderma (thick skin)
15. What is scleroderma?

- Autoimmune tissue damage with activation of fibroblast and deposition of collagen (fibrosis) that
thickens the tissue (also makes it tight and less mobile).

Inflammation Page 6.2

16.

Fig- scleroderma hands
17. What is diffuse type scleroderma? What are clinical presentation? How do you diagnose?

- Patient has diffuse skin and early visceral organ involvement.
- Esophagus most commonly affected - see solid and liquid dysphagia
- Diagnosis made by ANA and anti-DNA topoisomerase I antibody (aka SCL-70 antibody). SCL stands

for scleroderma.
17. What is localized type scleroderma? What are clinical presentation? How do you diagnose?

- Patient has local skin and late visceral organ involvement.
- Presentation (CREST)-

○ Calcinosis (calcification of skin), anti-centromere Ab
○ Raynaud phenomena
○ Esophageal dysmotility- see solid and liquid dysphagia
○ Sclerodactyly
○ Telangiectasis of skin
- Diagnosis made by anti-centromere antibody
Mixed connective tissue disease
18. What is mixed connective tissue disease? How is it diagnosed?
- It is autoimmune tissue damage with mixed features of SLE, scleroderma and polymyositis
(autoimmune damage of proximal muscles). Think of patient with bunch of autoimmune
condition.
- Diagnosis made by presence of antibodies against U1 ribonucleoprotein.

Inflammation Page 6.3

2.5 Wound Healing

1. What is regeneration?
- It's replacement of damaged tissue with native tissue.
2. What is repair?
- Repair is replacement of damaged tissue with fibrous scar. It occurs when tissue lacks

regenerative capacity or regenerative stem cells are lost.
3. What are 3 different types of tissue based on regeneration capacity?
- Labile tissue - they are continuously regenerating

○ Intestine - stem cell in mucosal crypt
○ Skin - stem cell in basal layer (most bottom layer of epidermis)
○ Bone marrow - hematopoietic stem cells (HSC). (HY - You can't identify HSC by microscope.

Presence of CD34 molecule tells it's HSC)
○ Lungs - stem cell is type 2 pneumocytes

Fig - circles are the crypts of bowel

Fig - line showing basal layer of skin
- Stable tissue - they don't continuously regenerate but have the ability to regenerate if needed.

○ Liver
○ Proximal tubule of kidney - pt on acute tubular necrosis are put on dialysis until their

proximal tubules regenerate
- Permanent tissue - can't regenerate

○ Myocardium
Skeletal muscle

Inflammation Page 7.1

○ Skeletal muscle
○ Neurons

4. What is granulation tissue (different from granuloma which occurs in chronic inflammation)?
What are 3 important cell types in it?

- It's present in early phase of repair. It contains -
○ Fibroblasts (deposit type 3 collagen)
○ Capillaries
○ Myofibroblast (contract wound)

Fig - granulation tissue showing blood vessels, collagen and fibroblast. Contrast it with granuloma
in chronic inflammation file.

5. What happens when granulation tissue is replaced by scar? What cofactor is needed?
- Collagenase removes type 3 collagen and replaces with type I collagen. It needs zinc as cofactor

(HY).

6. Where are 4 types of collagen found?
- Type 1 - bone (bone) - very high tensile strength
- Type 2 - cartilage (cartwolage)
- Type 3 - granulation tissue, embryonic tissue - very pliable/moldable
- Type 4 - basement membrane

7. How do regeneration and repair happen? What are some key molecules?
- They occur by paracrine signaling via growth factors. Some of them are

○ Fibroblast growth factor (FGF) - powerfully induces angiogenesis and skeletal development
○ VEGF - angiogenesis
○ PDGF - induces growth of endothelium, smooth muscle and fibroblast
○ TGF alpha - epithelial and fibroblast growth factor
○ TGF beta - inhibits inflammation, important fibroblast growth factor

8. Contrast wound healing by primary vs secondary intention.
- In primary intention, wound edges are brought together and there's minimum scar formation
- In secondary intention, edges are far away and granulation tissue fills the gap. Due to presence of

myofibroblasts, wound shrinks quite a lot.

9. Explain formation and structure of collagen.
- Collagen is formed as multiple alpha strands inside cells. Multiple alpha strands intertwine to

make procollagen and come outside cell.
- Structure of alpha strand is Gly-X-Y, where X and Y are proline and lycine.
- In extracellular space, multiple procollagen are crosslinked via hydroxyl groups in proline and

lycine to make collagen.

Inflammation Page 7.2

lycine to make collagen.
- Vitamin C is needed to hydroxylate proline and lysine.
- Crosslinking is done by lysyl oxidase which has copper as cofactor
10. What are some common causes of delayed wound healing? (HY)
- Infection is most common cause
- Vitamin C deficiency - causes poor hydroxylation of lycine and proline.
- Copper deficiency - lysyl oxidase can't cross link procollagen well
- Zinc deficiency - type III collagen can't be converted to type I by collagenase
- Foreign body, ischemia, diabetes, malnutrition etc
11. What is wound dehecence?
- Rupture of wound - commonly seen after abdominal surgery
12. What is hypertrophic scar
- Scar tissue being big but localized to wound. Caused by excess type I collagen

Fig- hypertrophic scar
13. Describe keloid (HY)?

- Scar tissue way out of proportion to the wound.
- Caused by excess type III collagen
- More common in african american
- Classically affects earlobes, face, and upper extremities.

Inflammation Page 7.3

Chapter 3: Principles of Neoplasia

3.1 Neoplasia

1. Define the following

Neoplasia - Neoplasia is cell growth that is monoclonal (arise from single cell),
unregulated, and irreversible.
- Contrast to hyperplasia (ex – hyperplasia of uterus during childbirth) which
is polyclonal and is regulated.

Desmoplasia - Process by which tumor becomes firm (it is because neoplastic cells induce
fibroblasts within the stroma to form abundant collagen)

Carcinoma in - (aka high-grade dysplasia) - when dysplastic changes involve entire
site thickness of epithelium (earliest form of epithelial malignancy)

2. What are two ways to determining monoclonality?
- G6PD or androgen receptor isoforms,
- Ig light chain phenotype for lymphomas.

3. How is monoclanity determined from G6PD?
- G6PD is a protein with multiple isoforms which is encoded in X-chromosome. Let’s say a

female has isoforms A and B in her 2 x chromosomes. Due to random silencing of X-
chromosomes, her A:B protein ratio in hyperplasia or normal condition will be 1:1. If the
ratio is different from 1:1, it strongly suggests monoclonality.

4. How is monoclonality determined from Ig light chain phenotype?
- The ratio of K to Lambda light chain is 3:1. If the ratio is different than this, it suggests

monoclonality

6. What are differences between benign and malignant neoplasm?

Benign neoplasia Malignant neoplasia

Remain localized and do not Invade locally and have potential to metastasize (don't

metastasize have to be already metastasized)

Slow-growing Rapid growing

Distinct Infiltrative

Mobile Fixed to surrounding tissue

7. Name the lineage of following benign and malignant tumors:

Cell lineage Benign Malignant (cancer)

Epithelium Adenoma Adenocarcinoma

Papilloma Papillary carcinoma

Mesenchyme Lipoma Liposarcoma

Angioma Angiosarcoma

Chondroma Chondrosarcoma

Osteoma Osteosarcoma

Lymphocyte doesn't exist Lymphoma

Melanocyte Nevus (mole) Melanoma (not melanosarcoma)

Neoplasia Page 1.1

Adenoma = tumor that makes glands
Papilloma = tumor that makes papillary finger like structures

8. What are leading cause of death in adults in children? (HY)

Adults Children

1. Cardiovascular disease 1. Accidents

2. Cancer 2. Cancer

3. Cerebrovascular disease 3. Congenital defects

9. What are leading cancers by incidence and death toll in male and females?
Cancer by incidence Male 1. Prostrate 2. Lung 3. Colorectal

Female 1. Breast 2. Lung 3. Colorectal

Cancer by death tolls Male 1. Lung 2. Prostrate 3. Colorectal

Female 1. Lung 2. Breast 3. Colorectal
- Table excludes squamous cell and basal cell carcinoma of skin - very common and

malignant but rarely metastasize. Detected early and easily treatable.
- Lung cancer doesn't have easy screening test like others. It's usually detected late.

10. What are some properties of neoplasia?
- Approximately 30 divisions before earliest symptoms arise (2^30 cells)
- Subsequent divisions results in increased mutations
- Cancers that don't produce symptoms till late (ex-ovarian, pancreatic, lung cancer- because
lots of space to expand) will have accumulated tons of mutations and hence poor prognosis

11. What area goals of cancer screening?
- Catch dysplasia before it becomes carcinoma (dysplasia is reversible)
- Detect carcinoma before clinical symptoms

Tests Detection

Pap smear - Cervical intraepithelial neoplasia

Mammography - Breast cancer
- Ductal carcinoma in-situ

PSA (prostrate specific - Prostrate cancer (usually grow on rectal side and doesn't
antigen) and DRE (digital produce urinary syndrome until late; BPH grows centrally
rectal exam) and produce urinary syndrome)

Hemoccult test and - Colorectal cancer
colonoscopy - Detect blood in stool (hemoccult test)

Neoplasia Page 1.2

3.2 Carcinogenesis (Part 1)

1. What do carcinogens do? What are examples?
- They damage DNA. Ex - chemicals, viruses, radiation.

2. What are cancer associations of the following chemicals? (HY)

Chemicals Cancer Remarks

Aflatoxins - Hepatocellular carcinoma (most common cancer - Derived from Aspergillus
in some African countries) flavus;
- Usually contaminates
stored grains

Alkylating - Leukemia - Found in chemotherapy
agents - Lymphoma drugs

Alcohol - Squamous cell carcinoma (SCC)of oropharynx and
upper esophagus(another risk is tobacco)
- Pancreatic carinoma (EtOH causes chronic
pancreatiis that incrases risk of cancer)
- Hepatocellular carcinoma

Arsenic - SCC of skin (women used to apply Arsenic to be
fair-skinned) - test Arsenic poisoning from
fingernail and hair follicles
- Lung cancer (Arsenic present in cigarettes)
- Angiosarcoma of liver

Asbestos - Lung cancer (far more likely) and mesothelioma

Cigarette - SCC of oropharynx and esophagus - MOST COMMON
- Lung cancer CARCINOGENIC
- Kidney and bladder cancer (urithelial carcinoma - WORLDWIDE
cells that line urinary tubes; most IMP risk factor: - Polycyclic hydrocarbons
cigerrate - toxins from smoking in urine irritate main carcinogen
the cells)

Nitrosamine - Stomach carcinoma (intestinal type) (other - Found in smoked food;
stomach carcinoma is diffuse type but responsible for high
nitrosamine not associated) stomach cancer in Japan

Napthylaine - Urothelial carcinoma of bladder - Derived from cigarette
smoke (excreted by
urine)

Vinyl chloride - Angiosarcoma of liver - Occupational exposure
(used to make PVC pipes)

Nickel, - Lung cancers - Occupational exposure
chromium,
beryllium, or
silica

- 1 Billion people smoke worldwide

3. What are ongogenic association of the following viruses?

Virus Cancer type

EBV - Nasopharyngeal carcinoma (Classic pt - Chinese male, African person) -

Neoplasia Page 2.1

EBV - Nasopharyngeal carcinoma (Classic pt - Chinese male, African person) -
metastasizes early; classic presentation is neck mass
HHV-8 - Burkitt lymphoma (Classic pt - African kids)
- CNS lymphoma in AIDS
HBV and HCV
HTLV-1 - Kaposi sarcoma (tumor of endothelial cell) (Classic pt - 1. older Eastern
HPV (type 16, european males - take tumor out; 2. AIDS pt - treat HIV; 3. transplant pt -
18, 31, 33) reduce immunosuppression)

- Hepatocellular carcinoma

- Adult T-cell lukemia/lymphoma

- SCC of anogenital area (vagina, vulva, cervix, anus)
- Adenocarcinoma of cervix

4. What are cancer association of ionizing and non-ioninzing radiation?

Radiation type Cancer types MOA

Ionizing (nuclear - AML - Generation of hydroxyl free radical
reactor, - CML
radiotherapy) - Papillary thyroid carcinoma
(Cherbonyl kids have lots of
papillary cancer)

Nonionizing (UBV - Basal cell carcinoma of skin - DNA damage (formation of too much
from sun most - SCC of skin pyrimidine dimers to be excised by
common) - Melanoma of skin restriction endonuclease)

- In xeroderma pigmentosum, restriction endonuclease is bad and pt has high risk of BCC, SCC and
melanoma of skin

5. What is most common cause of ionizing radiation in USA?

- Radon (formed by decay of uranium) - present in soil and accumulates in closed space (basement)
○ 2nd most common cause of lung cancer in USA

Neoplasia Page 2.2

3.2 Carcinogenesis (Part 2)

1. What are three systems to be disturbed in carcinogenesis? (HY)
- Proto-oncogene
- Tumor suppressor genes
- Regulator of apoptosis

Protooncogenes
2. What are protooncogenes and how can they cause cancer?
- Proto-oncogenes are essential for regular cell growth and differentiation
- Mutation produces oncogenes that leads to unregulated cell growth

3. What are examples of protooncogenes?
- Growth factors and their receptors
- Signal transducers
- Nuclear regulators (transcription factors)
- Cell cycle regulators (move cell division stuff around in cell)

- Normally, binding of growth factors to its receptor induces signal transduction. In
nucleus, cell cycle regulators are activated that induce cycling of cells through G1 - S -
G2 - M stages of cell division

4. What cancer are the following protooncogenes associated with and what's their
function and mechanism of causing cancer?

Cancer Function of MOA of cancer
protooncogene

Growth factor

PDGFB - Astrocytoma - Platelet derived Overexpression,
growth factor autocine loop

Growth factor
receptors

ERBB2 - Subset of breast Epidermal growth Amplification
(HER2/neu) cancer factor receptor

RET - MEN2A, MEN2B Neural growth factor Point mutation

- Sporadic MTC receptor

KIT - Gastrointestinal Stem cell growth Point mutation

stromal tumor factor receptor

Signal
Transducers

RAS gene family - Carcinoma GTP-binding protein Point mutation
- Melanoma
- Lymphoma
- (Found in ~70% of
all cancers)

ABL - CML Tyrosine kinase Translocation - t(9,22)

- Some ALL with BCR

Nuclear
regulators

C-MYC - Burkitt lymphoma Transcription factor T (8,14) involving IgH

Neoplasia Page 3.1

C-MYC - Burkitt lymphoma Transcription factor T (8,14) involving IgH
Transcription factor (heavy chain)
N-MYC - Neuroblastoma Transcription factor Amplification
L-MYC - Lung carcinoma Amplification
(small cell) Cyclin
Cell-cycle Cyclin dependent T(11, 14) involving IgH
regulators Mantle cell kinase Melanoma
CCND1 (cyclin carcinoma
D1) Melanoma
CDK4

Neoplasia Page 3.2

3.2 Carcinogenesis (Part 3), 3.4 Clinical Characteristics

1. Differentiate benign and malignant neoplasia.

Benign neoplasia Malignant neoplasia

Remain localized and do not Invade locally and have potential to metastasize (don't
metastasize have to be already metastasized)

Slow-growing (years) Rapid growing (weeks/months)

Distinct (well localized, ex - can isolate Infiltrative (can't distinguish from surrounding breast

by breast exam) tissue in physical exam)

Mobile (ex - you can grab a breast Fixed to surrounding tissue
tumor and move it around)

- Classification of benign vs malignant requires biopsy

2. What are histologic differences of benign and malignant tumor?

Benign neoplasia (well-differentiated) Malignant tumor (poor differentiation)

- Organized growth - Disoganized growth (doesn't look like tissue it's
growing in)

- Uniform nuclei - Nuclear pleomorphism with hyperchromasia (very
dark blue)

- Low nuclear to cytoplasm ratio (more - High nuclear to cytoplasm ratio (less cytoplasm, big
cytoplasm) nuclei)

- Minimum mitotic activity - High mitotic activity

- Lack of invasion - Invasion

- No metastatic potential

Fig: Follicular thyroid adenoma (left) - note organized cell growth with colloid in between cells,
uniform nuclei with lots of cytoplasm, minimum mitotic activity. Anaplastic thryoid carcinoma
(right) - disorganized growth (cells look nothing like thyroid), large nuclei:cytoplasm ratio, nuclear
pleomorphism, mitotic figure (very dark nuclei cell).

3. What's the absolute distinguishing feature between benign and malignant tumors?

Neoplasia Page 4.1

3. What's the absolute distinguishing feature between benign and malignant tumors?
- Potential to metastasize (benign tumors never metastasize, malignant tumors can metastasize)

3.5 What are some ways of identifying cell types in tumor?
- Immunohistochemistry
- Serum tumor markers

4. What is intermediate filament? How is immunohistochemistry of intermediate filament helpful in
grouping cancer? (HY)

- Intermediate filament are a type of cytoskeletal protein; different intermediate filament are
present in different cell types. -

- Immunohistochemistry of intermediate filament helps in identifying cell types in tumor.

Cell type Intermediate filament present

Epithelium Keratin

Mesenchyme (connective tissue) VImentin

Muscle Desmin

Neuroglia GFAP

Neurons Neurofilament

5. What immunohistochemical molecules help identify cancer of following cell types?

Cell type Immunohistochemistry
molecule

Prostrate PSA (prostrate surface antigen)

Breast epithelium ER (estrogen receptor)

Thyroid follicular cells Thyroglobulin

Neuroendocrine cells (small cell cancer of lung and carcinoid Chromogranin (HY)
tumor)

Melanoma S-100

- Well differentiated neuroendocrine tumor = carcinoid tumor. Poorly differentiated neuroendocrine
tumor = small cell cancer.

6. What are serum tumor markers and what's their utility?
- They are proteins released by tumors.
- Useful for

○ Screening (ex- high PSA) - still need biopsy for diagnosis
○ monitoring response to treatment (ex- PSA should drop after prostrate cancer surgery)
○ recurrence of tumor (ex - same pt returns 2 year later with bone pain; check for PSA to see if

it's prostrate cancer again)

7. What does tumor grading of well differentiated and poorly differentiated mean?
- Well differentiated - tumor resembles parent tissue - good prognosis
- Poorly differentiated - tumor doesn't resemble parent tissue - poor prognosis
- Look at cellular architecture and nuclear morphology to classify differentiation

8. What's staging of cancer? What's its value?
- Staging of cancer is based on size and spread
- It's no. 1 prognostic factor (more important than grade)
- Determined after final resection of tumor

Neoplasia Page 4.2

9. What's TNM staging of cancer?
- T = tumor size and depth (size important for solid organ tumor, and depth important for tubular

organs like colon)
- N = spread to regional lymph nodes (2nd most important prognostic factor)
- M = metastasis (no. 1 prognostic factor)

Neoplasia Page 4.3

3.3 Tumor progression

1. What are the steps in invasion and spread of tumor?
- Downregulation of e-kedherin (e-kedherin is an adhesion molecules that keeps epithelial cells

attached to each other)
- Tumor cells attach to laminin in basement membrane
- Tumor cells produce collagenase that destroys collagen 4 in basement mebrane. This helps tumor

pass through basement membrane
- Tumor cells bind to fibronectin in extracellular membrane and spread locally. It can now pass to

blood vessel or lymphatics.
2. How do metastatic cancer spread?
- Lymphatic spread is characteristic of carcinomas and less common for sarcoma.
- Hematogenous spread is characteristic of sarcoma and some carcinoma - usually follows venous

drainage and seeds at first capillary bed encountered
- Seeding of body cavities - most common is peritoneum (ex - by ovarian carcinoma (omental

caking)) but may also occur in the pleural or pericardial cavities, the subarachnoid space, and the
joint spaces

Fig: omental caking by ovarian carcinoma
3. What are carcinomas that spread hematogenously?
- Renal cell carcinoma - renal vein
- Hepatocellular carcinoma - hepatic vein
- Follicular thyroid carcinoma
- Choriocarcinoma (placental cancer - of trophoblast cells - function of placenta is to invade blood

vessels)

Neoplasia Page 5.1

Chapter 4: Hemostasis and Related
Disorders

CMAP summary

Hemostasis Page 1.1

4.1 Primary Hemostasis

Primary hemostasis - make a platelet plug
Secondary hemostasis - make fibrin mesh by coagulation cascade to stabilize platelet plug

1. What are steps of primary hemostasis?
- Vasoconstriction
- Platelet adhesion
- Platelet activation
- Platelet aggregation

2. What causes vasoconstriction?
- Vasoconstriction - mediated neurally and chemically. When endothelium is disrupted, endothelial

cells secrete endothelin for vasoconstriction. NO and prostacyclin production goes down (they
vasodialate).
- Endothelin - powerful vasoconstrictor
- NO and prostacyclin (prostaglandin I2)- vasodialator

3. What happens in platelet adhesion?
- Platelet adhesion - VWF (von willieband factor) is a glue that binds to exposed collagen in

damaged tissue. It then binds to glycoprotein VIII, and then glycoprotein IB (integrin IB) on
platelet. VWF mainly comes from endothelial cells storage unit - Weibel Palade body (HY), but are
also found in alpha granules platelets. (another important factor in weibel palade body is P-
selectin)

4. What happens in platelet activation (aka degranulation)?
- Platelet changes shape after adhesion and is activated. It secretes-

○ thromboxane A2 (very powerful degranulator made by cyclooxygenase (COX)),
○ alpha granules (contain fibrinogen and VWF),
○ delta granules (contain SAC - serotonin for vasoconstriction, ADP which is necessary for

expression of GP IIB/IIIA receptor by platelet and stimulates degranulation, and calcium that
helps in secondary hemostasis)

5. What happens in platelet aggregation?
- A single fibrinogen is linked to multiple platelets via their glycoprotein IIB/IIIA. This creates platelet

plug. Platelet plug is weak and needs secondary hemostasis (coagulation cascade) for stabilization.

6. What are 2 classification of platelet disorders?

Hemostasis Page 2.1

6. What are 2 classification of platelet disorders?
- Qualitative disorders - bad platelet
- Quantitative disorders - good platelet but too few in numbers (petechiae (spots in skin due to

bleeding) seen in thrombocytopenia and not usually in qualitative disorder)

6. What are common features of pt with problem in primary hemostasis ?
- Key sign is mucosal and skin bleeding; intracranial bleeding with severe thrombocytopenia (low

platelet) (can kill you).
- Mucosal bleeding - epistaxis (nose bleeding), hemoptysis (coughing blood), GI bleeding,

hematuria, and menorrhagia (heavy menses)
- Skin bleeding - petechiae (bleeding spots on skin), purpura (>3mm bleeding spots), ecchymoses

(>1cm), easy bruising.

7. What are some useful lab studies for platelet?
- Platelet count (normal is 150k-400k per microliter of blood)
- Bleeding time - prick patient and see how long it takes to stop bleeding - normal is 2-7 minute
- Blood smear - look under microscope
- Bone marrow biopsy - look at megakaryocytes (they make platelets)

Quantitative disorders
8. What is idiopathic thrombocytopenic purpura (ITP)?
- Most common cause of thrombocytopenia in kids and adults. Autoimmune production of IgG
against platelet antigens (ex- GP IIB/IIIA)
- Antibodies are made in spleen, and tagged platelets are phagocytosed by spleen macrophages.
Low platelets cause purpura (bleeding spots in skin)

9. Describe acute form of ITP?
- Seen in children weeks after viral infection or immunization.
- Self-limited disorder - resolves within weeks of presentation

10. Describe chronic form of ITP?
- Classically seen in child bearing age woman
- May be primary (idiopathic) or secondary (strong association with lupus- remember antibodies
against blood is a common feature in lupus)
- IgG can cross placenta and cause short-lived thrombocytopenia in children

11. What do we see in labs in ITP?
- Platelet count <50K/microliter
- Normal PT/PTT
- Hyperplasia of megakaryocytes on bone marrow biopsy

12. What are treatment choices of ITP?

Corticosteroids Kids respond well to corticosteroids, adults may show early response but
usually relapse

Hemostasis Page 2.2

IVIG (IV usually relapse
immunoglobulins)
Used for symptomatic bleeding. spleen macrophages will eat them instead
Splenectomy for of immunoglobulins bound to platelets.
severe cases
Recall that spleen is the source of Ab production and site of phagocytosis

Microangiopathic hemolytic anemia
11. What is microangiopathic hemolytic anemia (hemolysis in small blood vessels)? What 2 disease is

it commonly seen in?
- Platelet microthrombus are formed in small blood vessels that cut RBC as it passes through. This

results in hemolytic anemia with Schistocytes aka helmet cells (cut RBC).
- Thrombocytopenia is seen because of formation of tons of microthrombi.
- It's a symptom commonly seen in thrombotic thrombocytopenic purpura (TTP) and hemolytic

uremic syndrome (HUS)

Fig - schistocyte - the two pointy things at the end is classic appearance of cut RBC

12. What is thrombotic thrombocytopenic purpura?
- There are lots of thrombus in blood vessels that result in low platelet (thrombocytopenia) and
purpura (skin bleeding due to low platelet).

13. What causes thrombotic thrombocytopenic purpura (HY)?
- Caused due to deficiency ADAMTS13 enzyme. ADAMTS13 normally cleaves VWF multimers into
smaller monomers for eventual degradation. Bad ADAMTS13 = too much VWF = more platelet
adhesion resulting in microthrombi.
- Low ADAMTS13 is usually due to acquired autoantibody and most commonly seen in adult
females

13. What is hemolytic uremic syndrome (HUS)?
- Platelet microthrombi causes hemolysis. This mainly occurs in kidney leading to uremia and in
brain.

14. What causes HUS (HY)?
- Classically seen in children with E Coli 015:H7 dysentery - results from exposure to undercooked
beef. Dysentery = bloody diarrhea
- E Coli verotoxin damages endothelial cells in kidney and also reduces ADAMTS13 resulting platelet
microthrombi

15. What are clinical findings of TTP and HUS?
- Skin and mucosal bleeding
- Microangiopathic hemolytic anaemia

Hemostasis Page 2.3

- Microangiopathic hemolytic anaemia
- Renal insufficiency - predominant problem in HUS
- CNS abnormality - predominant problem in TTP
16. What do we see in labs in TTP and HUS?
- Thrombocytopenia with increased bleeding time
- Normal PT/PTT
- Anemia with schistocytes
- Increased megakaryocytes on bone marrow biopsy
17. How do we treat TTP?
- Plasmapheresis (process by which we remove protein from blood - removes Ab against

ADAMTS13)
- Corticosteroids - reduce production of AB.
Qualitative disorders of platelet
18. What is bernard soulier syndrome? How do we diagnose?
- Genetic GP1b deficiency; platelet adhesion is impaired
- Blood smear shows mild thrombocytopenia (platelet don't live as long because they lack GP1b)

with enlarged platelet. See big suckers in Bernard Soulier- big platelets

Fig: arrow points to big platelets in Bernard Soulier syndrome
19. What is Glanzmann thrombasthenia?

- Genetic GIIB/IIIA deficiency; platelet aggregation is impaired.
20. How do uremia affect platelet?

- It impairs adhesion and aggregation of platelets.

Hemostasis Page 2.4