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BMF III Pathology > Exam 1 > Flashcards

Exam 1 Flashcards

1
Q

Increase in Cell size and organ size is also known as

A

Hypertrophy

*inc. cell proteins

Examples:
1. Left ventricular (inc. systemic vascular resistance; hypertension)

  1. aortic stenosis (congenital bicuspid aortic valve or atherosclerosis)
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2
Q

Increase in Cell number

A

Hyperplasia

Examples:

  1. benign prostatic hyperplasia
  2. endometrial hyperplasia (estrogen)
    - -thickened endometrial stripe
  3. Secondary hyperparathyroidism due to low calcium and Vitamin D
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3
Q

Decrease in size or cell number as a result of catabolism of organelles and reduced cytosol volume

*autophagy

A

Atrophy

Examples:

  1. disuse atrophy in an injured limb
  2. atrophic brain in a patient w/ carotid stenosis and decreased brain perfusion; loss of innervation
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4
Q

Change from one cell type to another

A

Metaplasia

Examples:
1. Barrett esophagus
(change in distal 1/3 from squamous to intestinal; chronic gastric reflux)

  1. sqaumous metaplasia of proximal bronchi in smoker (ciliated, pseudostratified to squamous)
    - -may be precursor to squamous cell carcinoma
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5
Q

_______ is an ultimate determinant of cell injury and death as is consistent with fundamental osteopathic prinicpals

A

Hypoxia

hypoperfusion — hypoxia – ATP depletion — no energy for essential cell. functions

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6
Q

Causes of reversible cell injury

A

reduced ox phos and decreased ATP

*see cellular swelling and influx of water on histology

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7
Q

Causes of irreversible cell injury

A

increased cytosolic Calcium

  1. activates enzymes

(phospholipase, protease, endonuclease, caspases (apoptosis))

  1. increases mitochondrial permeability
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8
Q

Calcium enters the cytosol and acts as a cofactor, activating enzymes.

Cytochrome C enters the cytosol activating what enzymes?

A

Caspases

*apoptosis

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9
Q

What are the features of Coagulation necrosis?

A
  • -preserved architecture
  • -eosinophilic (histological stains)

ex: solid organ infarct (heart, organ, kidney, lung can appear hemorrhagic)

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10
Q

What are the 4 types of cellular adaptation?

A

Hypertrophy, Hyperplasia, Atrophy, Metaplasia

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11
Q

Reversible adaptations

A

Change in:

  1. size (hypertrophy)
  2. number (hyperplasia)
  3. phenotype (metaplasia)
  4. metabolic activity (metaplasia, hypertrophy)
  5. Function (all; lack of fxn)
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12
Q

Examples of Physiologic Hypertrophy (normal)

A
  1. inc. functional demand
    - -weight training
    - -inc. muscle mass
  2. hormones
    - -pregnant/gravid uterus
  3. growth factors
    - -normal growth
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13
Q

Examples of Physiologic Hyperplasia

A
  1. Hormones of GF’s
  2. Compensatory inc. after damage
  3. chronic irritation

ex: lactating breast
- endometrium-menstrual phase

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14
Q

Hyperplasia can be induced by chronic irritation. What are examples of this?

A
  1. Itchy skin
    - -thickened kertain layer (squamous)
    * *lichen simplex chronicus (pruigo nodularis)
  2. bronchial mucous gland
    - -smoking, asthma, COPD
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15
Q

Hyperplasia may also be induced by inappropriate or excessive actions of

a. hormones
b. growth factors
c. viruses
d. all of the above

A

answer: all of the above

* Abs and chemical imbalance

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16
Q

This hyperplastic disease is a result of increased androgen stimulation that leads to increased sensitivity to DHT

A

Benign prostatic hyperplasia

HPV (DNA virus)

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17
Q

This hyperplastic disease is caused by HPV and results in “lesions” on the skin

A

Verruca wart

*closely associated w/ dysplasia

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18
Q

This is hyperplasia that results from over-stimulated antibodies against thyroid hormone receptors

A

Graves disease (hyperthyroidism)

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19
Q

What are examples of hyperplasia that are due to physiologic chemical imbalance?

A
  1. Iodine deficiency
    –goiter
    (hyperplasia and hypertrophy)
  2. Compensatory parathyroid gland hyperplasia and Secondary hyperparathyroidism (from renal failure)
    - –Hypocalcemia, hyperphosphatemia
    - -due to lack of Vit. D
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20
Q

Physiologic atrophy includes

a. involution of a structure
b. formation of a ligament from embryonic/fetal structure
c. postpartum uterus
d. carotid stenosis

A

Answer: A-C

  • involution
  • pregnant uterus returning to normal size
  • lactating breast no longer producing milk
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21
Q

Atrophy becomes pathologic when which of the following occurs?

a. Loss of innervation
b. Diminished blood supply
c. Inadequate nutrition
d. Loss of endocrine stimulation
e. Occlusion of secretory ducts
f. Pressure

A

Answer: All of the above

A. Loss of innervation
—Amyotrophic lateral sclerosis (SK muscle; motor neuron loss)

E. Occlusion
—cystic fibrosis

F. Pressure
–ischemia

*no energy or energy producing substrates (aa’s, TG, CHO or electron acceptors)

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22
Q

A form of atrophy due to calorie malnutrition.

A

Marasmus

  • dec. somatic protein
  • extreme muscle wasting
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23
Q

A form of atrophy due to protein malnutrition

A

Kwashiorkor

–loss of albumin = loss of oncotic pressure

Symptoms: puffy, bloated, pot-bellied

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24
Q

True/False: Cerebral Atrophy can be a result of decreased blood flow from advanced age or from atherosclerotic disease in carotid arteries

A

True

  • also a cause of stroke
  • brain (slide 27 cell tissue)
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25
Q

Which of the following are cellular mechanisms that can lead to atrophy?

a. cell shrinkage from catabolism of organelles and reduced cytosol volume
b. undigested lipids stored as residual bodies
c. decreased protein synthesis
d. increased protein degradation

A

Answer: all

A. autophagy
B. Brown atrophy (lipofuscin)
–insufficient peroxidation – residual bodies

C. muscle wasting in cancer or TNF cytokines

D. ubuiquitin-proteosome pathway

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26
Q

_______ is a reversible change from one cell type to another. It occurs in differentiated cell types (epithelial, mesenchymal) and can be induced by altered differentiation pathways of proximal stem cells

A

Metaplasia

–adaptive response to changes in cellular env.

–LOF, inc. propensity for malignant transformation

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27
Q

Barret esophagus is a pathologic example of

A

Metaplasia (glandular)

*change in distal 1/3 of esophagus from squamous to intestinal type (columnar w/ goblet)

–inc risk for dysplasia

*chronic gastric reflux (heartburn)

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28
Q

What happens in squamous metaplasia of the proximal bronchi in a smoker?

A

The normal columnar respiratory mucosa changes to squamous epithelium

  • smoking, chronic bronchitis, squamous carcinoma
  • slide 30
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29
Q

______ is disorganized with abnormal maturation

A

Dysplasia

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30
Q

True/False: Cell injury can be due to ______:

  1. Oxygen deprivation
    - –hypoxia
  2. Physical agents
  3. Chemical agents
    - –Free radical injury (reactive oxygen species)
  4. Infectious agents
  5. Immunologic reactions
  6. Reactions to self and foreign (viral) antigens
  7. Genetic derangements
  8. Nutritional imbalances
A

True

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31
Q

What tissue are most susceptible to hypoxia?

A
  1. Brain
    - -watershed areas of cerebral vasculature
  2. Heart
    - -subendocardium
  3. Kidney
    - -PST, TAL
  4. Liver
    - -zone 3/central vein
  5. Colon
    - -splenic flexure
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32
Q

Reversible injury is characterized by reduced ox phos and decreased ATP.

It includes the following features:

  • Cellular swelling
  • Fatty changes

What are examples of each?

A

Cellular swelling:

  • hydropic change
  • vacuolar degeneration
  • dec. Na/K+ pump
  • dec. protein synthesis

Fatty changes

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33
Q

Irreversible cell injury occurs due to loss of the Ca2+ - ATPase pump as a result of lack of ATP. You also see increased cytosolic Calcium which activates the enzymes phospholipase, protease, endocnuclease and caspase.

What are the functions of these enzymes?

A

Phosphoipase: membrane damage

Protease: cytoskeleton damage

Endonucleases: damages nuclear chromatin

note: increased mitochondrial permeability and Cyt C release (activates caspases)

  • nuclear pyknosis
  • inner mit. membrane gradient lost
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34
Q

Cellular response to injry depens on the nature of the injury, and clinical consequences depend on the type and adaptability of the injured cell.

T/F: Reduction in ATP levels is fundamental to the process of cell injury and can lead to cell death

A

True

  1. ischemia: ATP depletion
  2. Hypoxia: dec. ATP production
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35
Q

Which of the following is an effect of ATP depletion?

a. Cellular swelling due to decreased activity of plasma membrane Na/K+ ATPase
b. Efflux of Ca2+
c. Increased protein synthesis

A

Answer: A

  • Influx of Ca2+ = enzyme activation
  • altered cell. metabolism (anaerobic glycolysis – lactic acid buildup)
  • reduced proteins synthesis
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36
Q

Which of the following is an effect of mitochondrial damage?

a. formation of mitochondrial permeability transition pore
b. loss of membrane potential in inner mito. membrane
c. formation of ROS
d. release of intramembranous proteins
e. None of the above

A

Answer: All

B. dec. ox phos and dec. ATP

D. intramembranous proteins: Cyt c
–sequestered bewteen membranes, activates apopstosis via caspase

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37
Q

What are the effects of Increased cytosolic Calcium in cells?

A

inc. mitochondrial permeability and activates enzymes which can harm the cell

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38
Q

Which of the following are examples of free radical damage due to ROS?

a. chemical and radiation injury
b. ischemia-reperfusion injury
c. inc. mitochondria

A

Answer: A and B

A. cancer treatment; acetaminophen

B. myocardial infarction

Also: normal cellular aging and normal phagocytic killing of microbes (inc. NADPH oxidase in phagolysosomes – neutrophils and monocytes)

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39
Q

Free radicals may be generated by:

a. normal metabolic processes
b. activated leukocytes in inflammation
c. metabolism of chemicals and drugs

What are examples?

A

Answer: all of the above

C. CCL4 converted to free radical in the liver (necrosis/fatty change)

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40
Q

How does ionizing radiation produce free radicals?

A

splits H2O into OH and H+

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41
Q

How do transition metals produce free radicals?

A

Iron overload — hemochromatosis

  1. Hereditary form = genetic abnormality in Fe absorption
    - –too much Fe absorbed in diet
  2. HFE C282 Y most common
    * too much Fe can produce OH
    * liver cirrhosis and pancreatic dysfunction

(diabetes, liver failure, cardiomyopathy, bronze skin, joint pain)

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42
Q

Describe how acetaminophen can generate free radicals and induce cell injury

A
  1. Cyt P450 – free radical intermediate (NAPQ1)
  2. Glutathione dec. NAPA1
    - –antioxidant
  3. Toxic drug levels overwhelm the liver
    - -reduce glutathione
    - -inc. toxic intermediate

**worsened by EtOH (upregulated P450 and inc. NAPQ1)

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43
Q

How does ethanol produce a fatty liver?

A

Increases NADPH

DHAP – glycerol #-P – fatty liver

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44
Q

The following are mechanisms by which free radicals are removed from the body:

  1. antioxidants
  2. spontaneously
  3. cellular enzymes

Give examples of antioxidants

A

-Vit. A, C, E

-protein binding of free Fe and Copper
minimized ability to generate ROS

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45
Q

The following are mechanisms by which free radicals are removed from the body:

  1. antioxidants
  2. spontaneously
  3. cellular enzymes

Spontaneous methods can be unstable and wane. What are examples of cellular enzymes?

A

Catalase, Superoxide dismutase, glutathione peroxidase

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46
Q

Which of the following is a pathologic effect of free radicals?

a. lipid peroxidation of membranes
b. oxidative modification of proteins
c. DNA damage

A

All of the above

DNA damage: if severe, cannot be corrected
–apoptosis

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47
Q

There are 2 forms of cell death: Necrosis and Apoptosis

Necrosis has characteristic and noteworthy patterns in different tissues depending on the type of injury. It involves cellular changes which can be seen grossly and histologically. What are these changes?

A

-degeneration of intracellular proteins

-enzymatic digestion of the cell
(lysosomes, WBC’s – autolysis)

  • **eosinophilia (H&E)
  • nuclear changes
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48
Q

What are the classic morphologic patterns of necrosis?

A
  • coagulative
  • liquifactive
  • caseous
  • fat
  • fibrinoid
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49
Q

Coagulative necrosis is necrosis that involves denaturation of enzymes and proteins as a result of

a. increased lactic acid
b. heavy metals
c. ionizing radiation
d. none of the above

NOTE: wedge shaped if involves dichotomous branching vessel

A

answer: all

–diminishes autolysis of cellular material

  • better architectural preservation
  • anucleate cells
  • hypereosinophilic

Examples: Pulmonary infarct, Renal infarct and Myocardial infarction (thrombosis in stenotic artery; LAD)

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50
Q

_________ necrosis is characterized by:

  1. dead cells digested
  2. leukocytes involved
  3. pus-like appearance
  4. bacterial and fungal infections
  5. hypoxia of CNS
A

Liquefactive necrosis

  • cerebral infarct - hypoxia of CNS
  • brain is unique
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51
Q

________ necrosis is characterized by

  1. variant of coagulation necrosis
  2. “cheese-like,” friable white material
  3. granulamotous inflammation
A

Caseous necrosis

Ex: mycobacterium TB

*also form of inflammation

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52
Q

______ necrosis (a.k.a. enzymatic ____ necrosis) is characterized by:

  1. focal areas of fat destruction
  2. released fatty acids that combine w/ Ca2+
  3. commonly seen in setting of pancreatitis
  4. can also be seen in dystrophic calcification
A

Fat necrosis

*also due to trauma
(Ca2+ in breast; abdomen in blunt trauma)

*pancreatitis: lipase and phospholipase; dystrophic calcification

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53
Q

________ necrosis often involves blood vessels. It is typically caused by an immune reaction.

Examples include: immune vasculitis, Rheumatic fever, malignant hypertension, pre-eclampsia and graft rejection

A

Fibrinoid necrosis

*small muscular arteries, arterioles, venules, glomerular capillaries

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54
Q

Apoptosis involves the activation of intrinsic enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins.

It is also known as prorammed cell death.

WHat are common triggers for apoptosis?

A
  • growth factor deprivation
  • DNA damage
  • protein misfolding
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55
Q

Which of the following are examples of normal apoptosis under physiologic conditions:

a. destruction of cells during embryogenesis
b. involution of hormone-dependent tissues upon withdrawal
c. cell loss in proliferating tissues
d. elimination of potentially harmful self-reactive lymphocytes

A

Answer: ALL

*also: short-lived cells of the immune response (neutrophils)

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56
Q

Apoptosis can be recognized histologically at the cellular level, but is characterized by a minimal host reaction (WON’T see inflammation).

What are the histologic features?

A

-cell shrinkage
-deeply eosinophilic cytoplasm
-chromatin condensation
(pyknotic nucleas, basophilia, karyorrhectic/fragmenting)

  • cytoplasmic blebs or formation of apoptotic bodies
  • results in phagocytosis
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57
Q

What are examples of apoptosis in pathology?

A

Infections: HBV, HCV

(acute hepatitis, cancers, autoimmune)

other bacterial and neurodegenerative diseases

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58
Q

Homeostasis depends on a balance b/t pro-apoptotic and anti-apoptotic proteins.

There are 2 pathways involved in apoptosis. Both converge with the release of what key enzymes? What are these 2 pathways?

A

***caspases

  1. mitochondrial pathway (intrinsic)
    –Cyt C
    (triggered by loss of survival signals, DNA damage, accumulation of misfolded proteins)
  2. Extrinsic
    - -FADD activates caspase
    - -death receptors (Fas, TNF)
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59
Q

What are examples of intracellular accumulations/inclusions?

A
  1. lipids (cholesterol)
  2. proteins (Igs, ubiquinated, amyloid)
  3. glycogen
  4. exogenous/endogenous pigments (melanin)
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60
Q

Intracellular lipid accumulation is assciated with what diseases?

A
  1. liver steatosis (lipid accumulation)
  2. diseases of abnormal metabolism
    - -diabetes
  3. ethanol
  4. cholesterolosis of gallbladder
  5. Xanthelasma
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61
Q

_______ is unmistakable with Prussian blue staining, but on H&E can be misinterpreted as lipofuscin. Both occur commonly in the liver and are brown

A

Iron

Diseases:

  • *hemochromatosis
  • macrophage accumulation (bruising; heart failure)
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62
Q

________ is polymers of lipids and phospholipids in a protein complex. It occurs by peroxidation of membrane lipids. It can arise from normal cellular turnover or from free radical damage

A

Lipofuscin

  • “wear and tear” pigment
  • heart and liver
  • no effect on cell. function
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63
Q

______ is derived from Hb and serves as the major storage form of iron (Fe2+). It is Iron stored w/ apoferritin protein to form ferritin micelles

A

Hemosiderin

  • aggregates of ferritin
  • synthesized and stored in macrophages, **bone marrow, liver hepatoctyes

NOTE: serum ferritin: reflects iron storage

*heart failure, hemochromatosis

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64
Q

_________ calcification occurs in abnormal tissue in the setting of a normal range plasma Ca2+ level. It can occur in areas of necrosis, atherosclerosis, damaged heart valves, or sites of granulomatous inflammation

A

Dystrophic calcification

*plasma Ca2+ = NORMAL

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65
Q

_________ calcification occurs in normal tissues in the setting of HYPERcalcemia.

A

Metastatic calcification

ex: hyperparathyroidism
(parathyroid tumor; PTH protein)

ex: bone resorption
ex: Vit-D disorders

ex: Renal failure
(retain phosphate; secondary hyperparathyroidism)

66
Q

________ is defined as “new growth” or a disorder of cell growth triggered by a series of acquired mutations affecting a single cell and its clonal progeny

A

Neoplasis

-tumor

67
Q

The following are characteristics of what kind of tumor?

  • indolent
  • amenable to surgical resection w/ unlikely recurrence
  • “oma” (typically)
A

Benign tumor

–mesenchymal consistent w/ phenotype or cell origin

–epithelial: vary in nomenclature

68
Q
  1. A benign tumor w/ fingerlike projections coming from an epithelial surface
  2. a benign tumor w/ a visible projection above a mucosal surface
  3. a benign tumor w/ various clinical implications based on context. However, it most often refers to a tumor of gland forming cells
  4. A benign tumor of adipose tissue (mesenchynal tissue)
A
  1. Papilloma
  2. Polyp
    - -some malignant tumors
  3. Adenoma
  4. Lipoma
69
Q

______ are cancerous. They can invade and destroy adjacent structures, spread to distant sites (metastasis), and cause death

A

Malignant tumors

70
Q

Malignant tumors:

  1. Tumors of mesenchymal origin are called ________
  2. Tumors of epithelial origin are called ______
  3. Leukemias
  4. Lymphomas
A
  1. Sarcoma
    - -osteosarcoma, leiomyosarcoma
  2. Carcinoma
    - -tissue type, organ involved, cell pattern

*not all malignant tumors have a benign counterpart

71
Q

These tumors form from divergent differentiation of a single clone or as a germ cell teratoma (all 3 germ layers)

A

Mixed tumors

Single clone: benign mixed tumor (pleomorphic adenoma of salivary gland; parotid)

Teratoma: (cystic teratoma)

72
Q

______ describes disorganized benign masses of cells that are in the appropriate anatomic location

A

Hamartoma

73
Q

______ describes heterotopic rests of cells that are NOT in the appropriate anatomical location

e.g. pancreas tissue in other areas of the GI tract

A

Choristoma

74
Q

Benign tumors can be differentiated from malignant tumors via histologic and microscopic assessment. What are common features of benign tumors?

A
  • well differentiated
  • resemble normal cell type morphology and function

e.g. lipoma (looks/feels like fat)

75
Q

Benign tumors can be differentiated from malignant tumors via histologic and microscopic assessment. What are common features of malignant tumors?

A
  • graded based on differentation
  • associated w/ necrosis
  • anaplasia (undifferentiated form)

NOTE: can be well differentiated (have to look to other features to define malignancy (needle biopsy))

76
Q

What are the features of anaplasia (a characteristic of malignant tumors)?

A
  1. pleomorphism (assume diff. forms)
  2. abnormal nuclear morphology
  3. abnormal mitoses
  4. loss of polarity
    ex: rhabdomyosarcoma
77
Q

________ is disordered growth (typically epithelium in adults; organs in peds). It is most commonly seen in surface epithelium of skin and mucosa

A

Dysplasia

78
Q

What are the features of dysplasia (disordered growth)?

A
  1. nuclear pleomorphism
  2. hyperchromasia (darkly stained nuclei)
  3. loss of polarity
  4. High N-C ratio
  5. abundant/inappropriately located mitotic figures

ex: carcinoma in situ (severe dysplasia)
ex2: hematopoietic cells can show dysplastic features (e.g. myelodysplasia)

79
Q

How is dysplasia graded?

A

mild, moderate, severe

Severe: carcinoma in situ

80
Q

Colonic adenocarcinoma is an example of what kind of tumor?

A

Malignant tumor

  • glands (abnormal)
  • irregular size/shape
  • hyperchromatic nuclei
81
Q

True/False: Dysplasia may be a precusor to malignancy, however, does not invariably progress to cancer

A

True

  • standardized grading for some tissues
  • once tumor cells breach basement membrane — invasice malignancy
82
Q

_______ tumors tend to be localized, grow in a cohesive pattern, and lack the ability to infiltrate, invade and metastasize. They can expand, however, and compromise function. On the other hand, ______ tumors can infiltrate, invade and destroy tissue and have the capacity to metastasize.

A
  1. Benign tumors
    - -capsule – slow progressive growth
  2. Malignant tumors
83
Q

Malignancy is determines based on the presence of what?

A
  • metastasis

- invasion

84
Q

Metastasis is defined as spread to sites that are physically discontinuous with the primary tumor.

It is the major determinate of cancer staging and prognosis (TNM system).

What determines the sites to which a cancer may metastasize?

A
  • anatomic and tumor specific features
  • vascular and lymph distribution
  • tissue specific homing
85
Q

What are the pathways of metastatic spread?

A
  1. hematogenous
  2. direct seeding of body cavities or surfaces
  3. lymphatic
86
Q

Metastasis via lymphatic spread is commonly seen with carcinomas (e.g. breast) and some sarcomas.

It is the major component of cancer staging. Describe spread via lymph.

A

-Sentinel node: first node in region to receive lymph flow from tumor
(breast – axilla)

-tumor cells in subcapsular sinus part of lymph node

87
Q

Metastasis via hematogenous (bloodstream) spread can occur in both sarcomas and carcinomas. Metastasis by this route is dependent on the anatomic vasculature.

Where does it spread?

A

–Bones

  1. paravertebral plexus (batson plexus)
    - -prostate
  2. axial skeleton
    - -ribs and vertebrae
    - -breast, prostate, lung

ex: colon – venous drainage to liver

88
Q

Most common cancer deaths in men and women

A

women:

  • lung
  • breast
  • colon and rectum

Males:

  • lung
  • breast
  • colon and rectum
89
Q

Most common cancer deaths in men and women

A

women:

  • lung
  • breast
  • colon and rectum

*reduced hormone replacement therapy

Males:

  • lung
  • prostate
  • colon and rectum

*use Prostate
antigen blood testing

*liver, thyroid, and melanoma on the rise

90
Q

What are the most dominant risk fasctors for cancer?

A

Environment

*genetic susceptibilitiy is related to env. influence

91
Q

Examples of Geographic variation

  1. China
  2. Japan
  3. Southeast Asia
  4. Sub-saharan Africa
A
  1. China
    - -nasopharyngeal carcinoma
    - -EBV
    - -esphageal squamous carcinoma
  2. Japan
    - gastric adenocarcinoma
    - -smoked food (nitrosamines)
  3. Southeast Asia
    - -hepatocell. carcinoma (HBV)
  4. Africa
    - -Burkitt lymphoma (EBV)
    - -Kaposi (HHV-8 w/ HIV)
92
Q

Environmental factors that influence cancer development

A
  1. infectious agents
  2. smoking
    - -up to 90% lung cancer deaths
  3. alcohol
    - -oropharynx, esophagus, larynx, liver
    - -synergism w/ cigarettes
  4. diet
  5. obesity
    - higher death rates
    - inc. breast and endometrial
    - inc. peripheral aromatase conversion of androgens to estrogens
  6. reproductive history
  7. environmental carcinogens
    - -UV radiation, occupational hazards

**asbestos: lung, mesothelioma

93
Q

True/False: Most cancers occur late in life. Longevity allows for the accumulation of somatic mutations

A

True

94
Q

Acquired pre-disposing conditions to cancer

A
  1. chronic inflammation
    - -inc. stem cells
    - -genotoxiv reactive O2 species
    - -metaplastic changes
    - clonal lymphocyte population (in response to insult)
  2. Precursor lesions
  3. Immunodeficiency states
    - -defecient T cell immunity
    - -viral induced neoplasia (HIV)
95
Q

Precursor lesions may arise in the background of chronic inlammation (e.g. Barret’s esophagus). However, cancer progression is not inevitable. If precursor lesions are amenable to treatment, cancer risk can be reduced.

What are recognizable and treatable precursor lesions?

A
  1. Barrett esophagus (esophageal carcinoma)
  2. Endometrial hyperplasia
    (endometrial adenocarcinoma)
  3. Leukoplakia
    (mucosal surfaces; squamous carcinoma)
  4. High grade cervical dysplasia
    - -cervical cancer
    - -seen on Pap
  5. Adenomatous GI polyps
    - -benign neoplasm to adenocarcinoma
96
Q

List the possible ways to prevent development of cancer

A
  1. lifestyle changes
  2. immunizations
  3. antioxidants
    (N-acetyl cystein; Vit. C, E)
  4. Cervical Pap smears, HPV testing
  5. Colonoscopy
    - -remove dysplastic polyps
  6. Screening
    - -low dose CT scanning (lung)
    - -mammography
  7. Digital rectal exam
  8. Treat pre-existing conditions
97
Q

Which of the following statements about cancer is true?

a. cancer is the result of non-lethal genetic damage
b. tumors are clonal
c. regulatory genes are involved in cancer mutations
d. cancer can occur secondary to LOF mutations in genes that normally maintain genomic stability or regulate the cell cycle

A

Answer: all of the above

*also carcinogenesis occurs in step-wise fashion

98
Q

Hallmarks of cancer

A
  1. avoid immune destruction
  2. evading growth suppression
  3. enabling replicative immortality
  4. tumor-promoting inflammation
  5. invasion and metastasis
  6. genomic instability
  7. induce angiogenesis
  8. resist cell death
  9. dregulate cellular energetics
  10. sustain proliferative signals
99
Q

Cancer cells acquire the capacity for autonomous growth. Proto-oncogenes play a role in this acquisition:

proto-oncogene – (mutation) oncogene – oncoprotein

What do oncogenes encode?

A

growth factor receptors
(receptor tyrosine kinases)

  • mutated form allow persistent tyrosine kinase activity
  • pro-growth oncoproteins allow self-sufficient growth
100
Q

EGFR is encoded by ERBB1.

Point mutations in ERBB1 are found in many cancers. These mutations result in constitutive ______ activity.

A

-constitutive tyrosine kinase activity

101
Q

What are drugs that can be used to block persistent tyrosine kinase activity caused by ERBB1 mutations?

A
  1. Colon adenocarcinoma
    - Cetuximab and Panitumumab
  2. Lung adenocarcinoma
    - -EGFR inhibitors in NSCLC w/ EGFR mutations
    a. Erlotinib (Tarceva)
    b. Afatinib (Gilotrif)
    c. Gefitinib (Iressa)
102
Q

True/False: HER2/neu is encoded by ERBB2. The gene is amplified leading to overexpression of HER2 receptor. Overexpression leads to constitutive tyrosine kinase activity.

A

True

  • testing = standard of care
  • Trastuzumab (Herceptin)
103
Q

RAS is a G-protein (GTP binding protein). Point mutations in the RAS family is the most common abnormality in proto-oncogenes.

Mutations cause what effects?

A

–reduce GTPase activity of RAS leaving it in an active state

–involved in 15-20% of human tumors

  • -90% pancreatic adenocarcinoma
  • -40-50% colon

–testing for KRAS and NRAS mutations in colon cancer (BRAF)
(EGFR inhibitors will not be effective)

104
Q

BCR-ABL is an oncogene created by a translocation. It results in chronic myelogenous leukemia.

How is it activated?

A
  • ABL = non-receptor tyrosine kinase
  • translocation of ABL = constiutive activation of kinase activity
  • Philadelphia chromosome
    (9: 22 BCR-ABL)
  • exposed concept of oncogene addiction
  • one of first diseases diagnosed and classified on a molecular basis

Tx: tyrosine kinase inhibitor (imatinib)

105
Q

Symptoms of chronic myelogenous leukemia (BCR-ABL)

A

older patient

  • high WBC count
  • left shifted peripheral blood population
  • neurtrophils and basophils
106
Q

Alterations in transcription factors such as MYC, a master transcriptional regulator can result in the activation of what?

A

–activation of cell growth genes (cell cycle, protein synthesis, reprogramming and upregulation)

  1. NMYC - neuroblastoma (pediatric malignancy of the adrenal gland)
  2. MYC - Brukitt lymphoma
107
Q

Tumor suppressor genes protect against unregulated cell growth.

Which of the following is correct about tumor suppressors?

a. inhibiting mitogenic signalling pathways
b. inhibiting cell cycle progression
c. inhibiting invasion and metastasis
d. inhibiting pro-growth metabolism and angiogenesis
e. DNA repair
f. genomic instability

A

Answer: all of the above

108
Q

Tumor suppressor genes protect against unregulated cell growth.

Which of the following is correct about tumor suppressors?

a. inhibiting mitogenic signalling pathways
b. inhibiting cell cycle progression
c. inhibiting invasion and metastasis
d. inhibiting pro-growth metabolism and angiogenesis
e. DNA repair
f. genomic instability

A

Answer: all of the above

**RB, p53

  • RB - regulates G1 to S checkpoint
  • -hyperphosphorylated: active
  • -hypophosphorylated: inactive
109
Q

Which of the following are protein products of tumor suppressor genes?

a. tf’s
b. cell cycle inhibitors
c. signal transduction molecules
d. WNT

A

Answer: A-C

*also, cell surface receptors and regulators of cell. responses to DNA damage

110
Q

RB is a tumor suppressor that is inactive when hypophosphorylated, and active when hyperphosphorylated.

The anti-proliferative effect of RB is removed by:

a. LOF function mutation
b. gene amplification of CDK 4 and cyclin D genes
c. loss of cyclin dependent kinase inhibitors (P16/INK4a)
d. viral oncoproteins that bind and inhibit RB (E7 protein of HPV)

A

Answer: All of the above

111
Q

This tumor suppressor gene is the most frequently mutated gene in cancer.

Most cancers have bi-allelic loss of function mutation in the TP53 gene.

A

p53

  1. Li Fraumeni
    - -loss of p53
    - -cancers of brain, sarcomas, leukemia, breast (under 50)
  2. p53 protein monitors for DNA damage, mutations
    - -cell cycle arrest
    - -DNA repair

*irreparable damage = apoptosis

112
Q

______ cells: Stem cells: bone marrow, skin, intestinal crypts

______ cells: G0 phase: liver, SM, endometrium

______ cells: cannot replicate, skeletal/cardiac muscle, neurons

A
  1. Labile cells
  2. Stable cells
  3. Permanent cells
113
Q

Adenomatous polyposis (familial polyposis syndrome) is a clinical example of a mutation in the APC tumor suppressor gene.

What are the features?

A
  • part of WNT
  • prevents nuclear transcription (via degradation of B-catenin)

Symptoms:

  • numerous colon polyps @ young age
  • high risk of colon, stomach cancer (100% penetrance)
  • sporadic colon cancer
  • somatic mutations
114
Q

Cancer cells prefer to undergo aerobic glycolysis because it provides dividing cells with metabolic intermediates for the synthesis of new cellular components. This is known as

A

Warburg effect

Normal cells: gf’s stimulate uptake of glucose and glutamine

Mutation: de-regulate this process

PET: exploits glucose hunger
*cancer staging

115
Q

Evasion of apoptosis is necessary for cancer cell development and survival. What mutations (in regulatory genes) allow this?

A

mutated BCL 2 (anti-apoptotic)

  • prevents Cyt C egress from mitochondria
  • survival and drug resistance
    ex: follicular B cell lymphoma
116
Q

There are 2 main mechanisms that cancer cells use to evade apoptosis: Intrinsic mechanism and Extrinsic mechanisms

Describe the intrinsic system

A
  • loss of p53
  • upregulate anti-apoptotic factors (BCL-2)
  • loss of APAF 1
  • upregulate apoptosis inhibitors
117
Q

There are 2 main mechanisms that cancer cells use to evade apoptosis: Intrinsic mechanism and Extrinsic mechanisms

Describe the extrinsic system

A
  • reduced CD 95 expression

- inactivation of death induced signalling complex

118
Q

Follicular B cell lymphoma is a cancer caused by overexpression of the BCL-2 protein.

What are its features?

A

t14: 18
- prevents apoptosis of B lymphocytes
- Cyt C doesn’t enter cytosol

119
Q

Tumors require O2 and nutrition to grow and to maintain viability of the primary tumor (and metastatic foci).

One of the ways by which they do this is via angiogenesis. How does this occur?

A
  • capillary sprouts from pre-existing capillaries
  • endothelial precursor cells

Influenced by:

  1. Hypoxia
    - VEGF
  2. Tumor suppressor and oncogenes
    - -p53 – loss of antiangiogenic factors (thrombospondin-1
120
Q

Drug that inhibits VEGF

A

Bevacizumab

Tx:

  • non-small cell lung (adeno)
  • metastatic colon
  • renal cell
  • Her 2 (-)
121
Q

What are factors that can stimulate angiogenesis

A
  1. TNF (from macrophages)
  2. chemotactic factors (tumor cells and macrophages)
  3. enzymes (proteases
122
Q

List the steps involved in invasion of the ECM by cancer cells

A
  1. Loosening of cell-cell contacts
    - -inactivates E-cadherin
  2. Degradation of ECM
    - -proteolytic enzymes (by tumor cells and stromal cells; matrix metalloproteinases, cathepsins)
  3. liberate growth, angiogenic and chemotactic factors
  4. Attachment to novel ECM components
    - -fibronectin
  5. Migration of tumor cells
    - –cytokines that stimulate locomotion
123
Q

True/False: Cancer cell migration involves intravasation (entry into the bloodstream) and extravasation (exit into tissue). During this process, they either evade or are destroyted by immune cells. Survivors form tumor emboli

A

True

124
Q

The following are potential determinants of where cancer may metastasize?

  1. anatomic factors
  2. cellular, subcellular factors

Explain

A
  1. Anatomic factors
    –1st capillary bed encountered
    –venous/lymph drainage
    (portal vein – liver; vena cava –lungs)
  2. Cell/Subcell
    - -ligands (target organs for specific adhesion molecule)
    - -chemokine receptors
    - -cell environment (unfavorable – spleen, SK muscle)
125
Q

Tumor antigens are important as they alow the body’s immune system to recognize a problem and to induce elimination.

Which of the following correctly describes tumor antigens?

a. products of mutated genes
b. overexpressed or abnormally expressed cell proteins
c. produced by oncogenic viruses
d. altered cell surface glycolipids/glycoproteins

A

All of the above

b. overexpressed
- -tyorsinase; MART (melanoma)

c. HPV, EBV

Also:
-Cell type specific differentiation antigens (CD 20 in B cell lymphoma)

-Oncofetal antigens (tumor markers - CEA, AFP)

126
Q

Anti-tumor activity is mediated predominantly by

A

Cell-mediated T cells

  • MHC I
  • CD 8 Cyt T cells
127
Q

How do Tumors evade the immune system? \

a. induce apoptosis
b. immunoediting
c. reduced MHC molecules
d. activate immunoregulatory pathways

A

Answer: B, C, D

b. Immunoediting
- -select Ag-negative variants

c. dec. MHC

d. Immunoregulatory pathways
- -PD-1 (inhibit T cells)
- -downregulate immune
- -secrete immunosuppressive factors (TGF-B)

128
Q

PD-1 inhibitors (checkpoint therapy) include

A
  1. Pembrolizumab (Keytruda)
    –metastatic
    (melonama, NSCLC)

–companion diagnostic test

  1. Nivolumab
  2. Optivo
    - -metastatic (melanoma, NSCLC, Renal cell carcinoma)
129
Q

An inherently unstable genome pre-disposes to mutations and subsequent neoplasia. Genetic alterations leading to increased mutation are commonly seen in cancers.

What are examples?

A
  1. Genetic alterations

- -BRCA mutations (genomic instability)

130
Q

An inherently unstable genome pre-disposes to mutations and subsequent neoplasia.

Defects in DNA repair can increase the risk of neoplasia. What is an example?

A

Hereditary non-polyposis coli (Lynch syndrome)

–defect in DNA mismatch repair (MMR genes)

–autosomal dominant

–colon and endometrial cancer

131
Q

Xeroderma pigmentosa is caused by genomic instability. What is its mechanism?

A

inability to repair pyrimidine dimers

  • -UVB radiaiton
  • -autosomal recessive
132
Q

Epigenetic changes can affect gene expression by:

a. hypermethylation of tumor suppressor genes
b. histone modification
c. differentiation
d. self-renewal
e. drug sensitiviy/resistance

A

Answer: all of the above

*hypermethylation and histone modification - major

133
Q

Cigarettes are one of the most important carcinogens known and are involves in some of the most frequently sen cancers in health care.

What is the most common carcinogen implicated in smoking illnesses and what are common illnesses?

A

Polycyclic hydrocarbons

  • head and neck squamous carcinoma
  • lung and pleura
134
Q

Carcinogens can be direct acting or indirect acting.

  1. In ______-acting, conversion is not required. An example is alkylating agents.
  2. In _____-acting, conversion/metabolism is required. It is associated with p450 polymorphisms in patients. Examples include polycyclic hydrocarbons (benzo-a-pyrene, aromatic amines and azo dyes.
A
  1. Direct acting
  2. Indirect-acting

NOTE: indirect acting carcinogens are also considered initiators of carcinogenesis because they create a mutation

135
Q

What are the steps in cancer formation?

A
  1. Initiation:
    - irreversible mutation
  2. Promotion:
    - stimulates cells to enter cell cycle
    - -tumors continue to replicate

–ex: promoters of hyperplasia (estrogen)

*promoters cannot induce cancer on their own

  1. Progression
    - development of tumor heterogeneity
    - –continued replication inc. chances of selecting for favorable growth attributes
136
Q

There are different types of radiation carcinogenesis including:

  1. Ionizing radiation
  2. UV radiation

Describe ionizing radiation

A

*Initiator of carcinogenesis

  • produces hydroxyl free radical
  • DNA injury
  • chromosome breakage

-occupational hazards (radiology, nuclear materials)

Example: leukemias, papillary thyroid carcinoma, lung, breast, liver

137
Q

What are examples of initatiors of carcinogenesis?

A
  • UVB radiation
  • Nitrosamines
  • asbestos
  • polycyclic hydrocarbons
  • HPV
138
Q

There are different types of radiation carcinogenesis including:

  1. Ionizing radiation
  2. UV radiation

Describe UV radiation

A
  • UVB forms pyrimidine dimers
  • actinic damage leads to sun-related skin cancers

Examples: melanoma, squamous cell and basal cell carcinomas

139
Q

Microbial carcinogens include:

  1. bacteria
  2. parasites
  3. viruses

What are common examples of bacterial carcinogens?

A

H. pylori

gastric adenocarcinoma and lymphoma

140
Q

Microbial carcinogens include:

  1. bacteria
  2. parasites
  3. viruses

What are common examples of parasitic carcinogens?

A
  1. Schistosoma hematobium
    - -squamous carcinoma of bladder
  2. Clonorchis sinensis and Opisthorchis viverrini
    - -bile duct carcinoma
141
Q

Microbial carcinogens include:

  1. bacteria
  2. parasites
  3. viruses

What are common examples of viral carcinogens?

A
  1. DNA
    - -EBV (Burkitt – translocation of MYC)
    - -HPV
    - -HBV
  2. RNA
    - -HTL-V-1
    - -HCV

NOTE: HCV and HBV have multi-factorial pathogenesis – chronic inflammation, inc. cell death, inc. cell turnover)

142
Q

Human papillomavirus (HPV) is involved in

  1. benign squamous papillomas (warts)
  2. Genital warts (condylomas)
  3. Cancers of the cervix, anogenital region, head and neck

Which strains are involved with each disease?

A
  1. HPV 1, 2, 4, 7
  2. HPV 6, 11
  3. HPV 16, 18

Vaccines:

  • recombinant with 4, 9
  • Most important: 16, 18, 31, 33

*L1 capsid in vaccine results in production of viral-like particles to which the body produces immune response

143
Q

HPV is able to randomly integrate into the genome of the host without consistent association with a proto-oncogene.

These viral-integrated cells show genomic instability, leading to overexpression of ____ and ____ oncoproteins.

A
  • overexpresion of E6 and E7 oncoproteins
  • inactivate tumor suppressors (RB, p53)
  • activate cyclins
  • inhibit apoptosis
  • reduce senescence
144
Q

Epstein Barr virus (EBV) is a DNA herpes virus that infects B lymphocytes and some epithelial cells.

It causes what cancer?

A
  • Burkitt lymphoma (endemic)
  • translocation 8; 14 inc. MYC
  • B cell lympoma in immunocompromised
  • some Hodgkin, nasopharyngeal carcinoma
145
Q

Although not common, physical injury or trauma may be associated with neoplasia.

The causes are most likely multi-factorial. What are examples of cancers developed from physical injury or trauma?

A

-squamous carcinoma

Causes:

  1. 3rd degree burn
  2. chronic inflammation:
    - inc. stem cells
    - genotoxic ROS
    - bacterial products (osteomyelitis, draining sinuses)
146
Q

The following include clinical effects of cancer:

  1. cachexia
  2. hemostasis abnormalities
  3. paraneoplastic syndromes

_______ is a generalized catabolic process that is characterized by anorexia, muscle wasting, loss of subcu adipose tissue, and fatigue.

A

Cachexia

Cancer cells release mediators:

  • TNF-alpha
  • PIF (ubiquitin proteasome pathway)
  • LIF (inc. TNF-a)
147
Q

The following include clinical effects of cancer:

  1. cachexia
  2. hemostasis abnormalities
  3. paraneoplastic syndromes

________ of chronic disease involves hepcidin. It can also be related to iron deficiency (bleeding, GI loss).

A

Anemia

  1. macrocytic
    - -folate loss (for RBC synthesis)
  2. hemolytic
    - -cold agglutinins
148
Q

The following include clinical effects of cancer:

  1. cachexia
  2. hemostasis abnormalities
  3. paraneoplastic syndromes

_______ occurs when cancer creates a thrombophilic state and becomes hypercoagulable. This increases the risk for DVT, blood clots, and disseminated intravascular coagulation (DIC).

A

hemostasis abnormalities

  • deep vein thrombosis
  • blood clots
  • DIC
149
Q

The following include clinical effects of cancer:

  1. cachexia
  2. hemostasis abnormalities
  3. paraneoplastic syndromes

________ are clinical signs that are distant from or otherwise not attributable to anatomic or functional location of the primary (metastatic tumor). It involves 10% of cancer patients and is a significant cause of morbidity.

A

Paraneoplastic syndromes

–mimics metastatic disease
(hypercalcemia)

–earliest manifestation of occult cancer

–ectopic hormone and hormonal effects are most common (endocrinopathies)

150
Q

Paraneoplastic syndromes include SiADH and Cushing syndrome.

What are their features?

A
  1. SiADH
    - -hyponatremia
    - -small cell carcinoma of lung
  2. Cushing
    - -small cell carcinoma
    - -increase corticotropin and POMC
    - –too much cortisol
151
Q

Hypercalcemia is a paraneoplastic syndrome associated w/ what cancers?

a. squamous carcinoma of the lung
b. breast carcinoma
c. renal carcinoma
d. small cell carcinoma

A

Answer: A, B, C

  • Parathyroid hormone related protein
  • other cytokine effects - IL-1, TNF, TGF-a

(endocrinopathy)

152
Q

________ is a paraneoplastic syndrome characterized by patches of dark, thickened, hyperkeratotic skin. It is related to insulin-like growth factor (IGF-1) and is not specific to cancer.

A

Acanthosis nigricans

  • gastric, lung, uterine carcinoma
  • immunologic
  • IGF-1
153
Q

_______ is a paraneoplastic syndrome seen in lung carcinoma. It involves a periosteal reaction of the distal phalanx. Clubbing may also be seen.

A

Hypertrophic osteoarthropathy

  • fingers
  • not specific to cancers
154
Q

Tumor markers, or biomarkers can contribute to detection of cancer, though are not used for definitive diagnosis.

When are they used?

A
  1. detection
    - -PSA as screening test
  2. determine effectiveness of therapy
  3. monitor recurrence
  4. estimate tumor burden (LDH in lymphoma)
  5. clinical stagning (LDH and hcG in testicular tumors)
    * not specific to one disease process, but have limited diagnostic differential
155
Q

Examples of tumor markers (biomarkers)

A
  1. AFP
    - hepatocell. carcinoma
    - yolk sac tumors of ovary and testes
  2. CEA
    - colorectal and pancreatic cancers
    - -monitor for recurrence
    - -lung and stomach too
  3. PSA
    - prostate cancer and hyperplasia
    - -quantity is important
156
Q

What are the criteria for cancer grade?

a. degree of differentiation
b. invasiveness
c. nuclear features
d. all of the above

A

All of the above

  1. differentiation
    - -how well do cells resemble normal cells
  2. invasiveness
    - -does the tumor breach the BM or invade into vessels?
  3. Nuclear
    - -enlargement (high N to C)
    - -chromatin clump
    - -abnormal mitotic figures
    - -hyperchromasia (dark nucleus)
157
Q

Cancer staging uses the TNM system. Staging is the most important prognostic indicator.

What are the criteria for staging?

A

T: tumor (size)
N: nodal involvement
M: Metastasis

M > N > T

*PET scanning after initial diagnosis (can detect metastatic disease)

158
Q

Laboratory diagnosis of cancer involves many techniques. What is the gold standard?

A

Tissue biopsy (needle)

  • needle, open, surgical excision, fine needle aspiration
  • all H&E stain
159
Q

Ancillary techniques used to interrogate tissue samples include

a. special stains
b. immunohistochemistry to exploit varying specificitis of antigen expression
c. In situ hybridization and gene amplification (ex: HER2)

A

all of the above

160
Q

Molecular diagnostics of cancer include

  1. diagnosis and prognosis
  2. detection of minimal residual disease
  3. hereditary predispositon to cancer
  4. RNA expression profiling
  5. DNA sequencing
  6. DNA copy number

Give examples of each (if applicable)

A
  1. FISH for t(14;18) in follicular B cell lymphoma
  2. BCR-ABL transcripts in CML
  3. BRCA 1/2
  4. Next Gen sequencing

BMF III Pathology (2 decks)

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