1
Q
Intrinsic Mitochondrial Apoptosis Pathway
A
- occurs after a regulating factor is withdrawn from cell population, exposure to injurious stimuli (DNA damage = radiation, toxins, free radicals, hypoxia), protein misfolding (ER stress)
- BCL2 = antiapoptotic, BAX & BAK = pro apoptotic
- BCL2 sits on mitochondrial membrane and binds to APAF1 to inhibit release of cytochrome C
- when cell injury occurs BAX and BAK dislodge BCL2 and form a pore that allows release of Cytochrome C which activates initiator caspases then executationer caspases causing cell break down
- Caspases 9 and Cytochrome C specific
2
Q
Extrinsic Death Receptor Apoptotic Pathway
A
- there are 2 pathways which are FasLigand binding or immune cell (CD8 release of perforin and granzymes)
- these activate FADD and adaptor proteins that activate inactive caspases and then executioner caspases to allow for apoptosis
- Caspases 8 specific
Ex: Negative T-cell Selection in thymus
3
Q
Characteristics of Apoptosis
A
- deeply eosinophilic cytoplasm = pink cytoplasm
- cell shrinkage
- nuclear shrinkage (pyknosis)
- basophilia
- membrane blebbing
- nuclear fragmentation (karyorrhexis)
- Formation of apoptotic body that is phagocytosis
4
Q
Necrosis
A
- doesn’t make decision for cell death = passive response to injury and no energy required
- always pathological
- occurs sporadically
- enzymatic degradation and protein desaturation of cell due to exogenous injury
- there is a leak of cell contents through damaged plasma membrane in to extra cellular space ==> inflammation
- overall unlregulated cell death from = damage to cell membranes, loss of ion homeostasis, desaturation of cellular proteins
5
Q
Coagulative Necrosis
A
- Ischemia/infarcts in most tissues except brain
- due to denatured proteins and then enzymatic degradation
- cell outline is preserved and there is increased cytoplasmic binding of acidophillic dyes = no nucleus found
- area of infarct is often wedge shaped
- red infarction = blood re-enters loosely organized tissue = testicle and lungs
6
Q
Liquefactive Necrosis
A
- Bacterial abscesses, pancreatitis, and Brain infarcts (micro glial cells digest infarcted brain tissue)
- due to neutrophils that release lysosomal enzymes that digest the tissue, enzymatic degradation first, and then proteins denature
- Histo: Early –> cellular debris and macrophages. Late –> cystic spaces and cavitation
7
Q
Caseous Necrosis
A
- from TB or Systemic fungi (histoplasmosis), Nocardia
- due to macrophages that wall off the infecting microorganism –> granular debris
- fragmented cells and debris surrounded by lymphocytes and macrophages
- soft and friable necrotic tissue with cottage cheese like appearance
8
Q
Fat Necrosis
A
- Enzymatic = acute pancreatitis or Nonenzymatic = breast trauma
- in breast fat necrosis can present as a mass
- damaged fat releases lipase so which breaks down fatty acids in cell membranes. Fatty acids attract calcium
- Histo: outline of dead fat cells without peripheral nuclei; saponification of fat with calcium
- appears dark blue on H&E
- necrotic adipose tissue attract calcium = fat sapinofication
9
Q
Fibrinoid Necrosis
A
Necrotic damage to blood vessel wall
- immune reactions in vessels (inflammatory process involving arteries) or malignant hypertension
- immune complexes combine with fibrin –> vessel wall damage
- Histo: vessel walls are thick and pink
- can also be seen in young women that have pre-eclampsia = fibrinoid necrosis of the placental blood vessels
10
Q
Gangrenous Necrosis
A
- distal extremity after chronic ischemia
- Dry = ischemia ==> coagulative
- Wet = superinfection of dead ischemic tissue ==> liquefactive
11
Q
Apoptosis vs. Necrosis
A
Apoptosis: regulated, usually physiologic, plasma membrane remains intact, no leakage, and no inflmmatory reaction, uses energy
Necrosis = passive response to injury, always pathological, disruption of plasma membrane, cell swelling, no phagocytosis, leakage of contents, inflammatory response
12
Q
Chromatolysis
A
- involves neuronal cell body following axon injury
- changes reflect an increase in protein synthesis in effort to repair the damaged axon
- Characterized by: round cellular swelling displacement of the nucleus to the periphery, dispersion of Nissl substance throughout cytoplasm
13
Q
Pathological Calcifications
A
Dystrophic = calcium deposition in abnormal tissues after injury or necrosis, tends to be localized, patient is normally normocalcemic
Metastatic = widespread calcium deposition in normal tissues, secondary to hypercalcemia or high calcium phosphate production levels
- affects tissues that lose acid quickly and are alkaline ==> kidney , lung, and gastric mucosa
14
Q
Leukocyte Extravasation
A
- occurs at post capillary venues
- margination and rolling, tight binding, diapedesis, and migration
15
Q
Scar Formation
A
- 70-80% of tensile strength regained at 3 months, little will be regained after
Two types of Scars - hypertrophic scars = slight increase in collagen synthesis, parallel collagen arrangement, confined to borders of original wound, infrequently recur after resection
- Keloid scars = very increased collagen synthesis, disorganized collagen arrangement, extends beyond borders of original wound, frequently recur after resection, and higher incident in AA.
16
Q
Exudate vs. Transudate
A
Exudate = due to lymphatic obstruction, inflammation/infection, malignancy
- protein rich, cellular
- high specific gravity
Transudate = thin, due to increased hydrostatic pressure or decreased oncotic pressure, sodium retention
- hypo cellular
- protein poor
- decreased specific gravity
17
Q
Amyloidosis
A
- abnormal aggregation of proteins into beta pleated sheaths–> damage and apoptosis
- AL (primary) = due to deposition of proteins from Ig Light chains
- AA (secondary) = due to chronic inflammatory conditions. Composed of serum amyloid A
- Dialysis related = fibrils composed of B2-micro globulin in ESRD patients. Deposits in joints. Can cause carpal tunnel
- Heritable = due to transthyretin gene mutation
- Age-related (senile) systemic = due to deposition of normal wild type transthyretin in myocardium and other sites. Slower progression of cardiac dysfunction relative to AL amyloidsis
- Familial amyloid cardiomyopathy = mutated serum transthyretrin deposits in the heart leading to restrictive cardiomyopathy
- Organ specific = amyloid deposition in a single organ. (Beta amyloid protein clever from Amyloid precursor protein APP = Alzheimer’s disease) or (Islet amyloid polypeptide from insulin = Diabetes type 2 caused by deposition of amyloid in pancreatic islets)
- medullary carcinoma of the thyroid = calcitonin produced by tumor cells deposits within the tumor (tumor cells in an amyloid background)
18
Q
Lipofuscin
A
- yellow brown wear and tear pigment seen in normal aging
- formed by oxidation and polymerization of auto phagocytosis organelles membranes
- will see deposits in biopsy of autopsy in an elder person
19
Q
P-glycoprotein
A
- also known as multi drug resistance protein 1 (MDR1)
- classically seen in adrenal cell carcinoma but also expressed by other cells
- used to pump out toxins including chemo drugs
20
Q
Plasia’s
A
- dysplasia, hyperplasia, and meta plasia = reversible
- anaplasia, neoplasia, and desmoplasia = irreversible
- desmoplasia = fibrous tissue formation in response to neoplasm
21
Q
Tumor Nomenclature
A
Carcinoma
- from epithelial origin
- spreads via lymphatics
Sarcoma
- spread hematogenously
- mesenchymal origin
Hamartoma = disorganized overgrowth of tissues in their native location
Choristoma = normal tissue in a foreign location
22
Q
Common metastases
A
Lung> Breast> Prostate> Melanoma > GI ===> metastasize to the Brain
Colon» stomach> pancreas ===> Liver
Prostate, breast> lung, thyroid, kidney ==> Bone (predilection for axial skeleton) = usually osteolytic except prostate
23
Q
Meta plasia
A
- apocrine metaplasia of breast due to fibrocystic changes = no increased rink of cancer
- Vitamin A deficiency can result in metaplasia = results in metaplasia of conjunctiva which causes a thickening and change from goblet/cell columnar epithelium of conjunctiva to the keratinizing squamous epithelium ==> keratomalacia
Keratomalacia = dry eyes that can lead to destruction of cornea and blindness
Mesenchymal tissues can also undergo metaplasia
- myositis ossificans = inflammation of skeletal muscle results in meta plastic production of bone in skeletal muscle
24
Q
Carbon Monoxide Poisoning
A
CO binds hemoglobin binds more avidly than oxygen
PaO2 normal but SaO2
- exposures include smoke from fires and exhaust from cars or gas heaters
- Classic finding = cherry red appearance of skin
- Early sign of exposure = headache
- significant exposure = leads to coma and death
25
Reversible Injury
- cellular swelling = leads to loss of micro villi and membrane blebbing
- swelling of RER results in dissociation of ribosomes and decreased protein synthesis
26
Irreversible Injury
- Hallmark = membrane damage
- plasma membrane damage = cytosolic enzymes leak into serum and additional calcium entering cell
- mitochondrial membrane damage = loss of ETC chain (inner mitochondrial membrane) and cytochrome c leaking into cytosol (activates apoptosis)
- lysosomal membrane damage = hydrologic enzymes leaking into cytosol which is activated by high intra cellular calcium
27
Cell death
Hallmark = loss of the nucleus
- nuclear condensation (pyknosis)
- fragmentation (karyorrhexis)
- dissolution (karyolysis)
28
CCl4 Free Radical injury
- converted to CCl3 by CYP450 hepatocytes
- results in cell injury with swelling of RER, causing ribosomal detachment, and impaired protein synthesis
- decreased apolipoproteins lead to fatty changes in the liver
29
Familial Mediterranean Fever
- autosomal recessive
- dysfunction of neutrophils
- occurs in person's of Mediterranean origin
- presents with episodes of fever and acute serosa leukemia inflammation
- High SAA during attacks deposits as AA amyloid
30
Alfatoxin
- from aspergillus that can contaminate stored rice and grains
- causes Hepatocellular carcinoma
31
Arsenic
- from cigarette smoke
| - causes squamous cell cancer of skin, lung, cancer, and angiosarcoma of liver
32
Nitrosamines
- found in smoked foods and is responsible for high rates of stomach cancer in Japan
- associated with intestinal type of stomach cancer
33
Napthylamine
- from cigarrette smoke
| - urothelial carcinoma of bladder
34
Vinyl Chloride
- occupational exposure used to make polyvinyl chloride for use in pipes
- causes angiosarcoma of liver
35
Oncogenic Viruses
EBV = nasopharyngeal carcinoma, Burkett lymphoma, and CNS lymphoma in AIDS
HHV-8 = kaposi sarcoma
HBV and HCV = hepatocellular carcinoma
HTLV1- Adult T-cell leukemia/lymphoma
High Risk HPV = squamous cell carcinoma of Vulva, vagina, anus, and cervix
36
Radiation
Ionizing = nuclear accidents and radiotherapy
- generates hydroxyl free radicals
- AML, CML, and papillary carcinoma of thyroid
- activates the G2/M checkpoint resulting in chromosomal abnormalities in mitosis
Nonionizing (UVB sunlight)
- results in formation of pyrmidine diners which are normally excised by restriction endonucelases = Xeroderma Pigmenetosum
- Basal cell carcinoma, Squamous cell carcinoma, melanoma of skin
37
Categories of OncogenEs
- Growth Factor
- Growth Factor receptors
- Signal Transducers
- Nuclear regulators
- Cell cycle regulators
READ PAGE 26 on PATHOMA
38
Retinoblastoma
- holds the E2F transcription factor that is necessary for transition from G to S phase
- E2F is released when RB is phosphorylates by Cyclin D or CDK complex
- Both copies of RB gene must be knocked out for tumor formation
- Sporadic mutation (both hits are somatic) = unilateral retinoblastoma
- Germline mutation (2nd hit is somatic) = familial retinoblastoma ==> bilateral retinoblastoma and osteosarcoma
39
Follicular Lymphoma
- t(14,18)
- over expression of BCL2 (on 18)
- prohibition of apoptosis
- B cells that normally undergo apoptosis during somatic hyper mutation in the lymph node germinal center accumulate leading to lymphoma
40
Tumor Invasion and Spread
1. Tumor cell down regulates E-Catherine
2. The tumor cell attaches to laminitis and destroys basement membrane type 4 collagen via collagense
3. Tumor cell attaches to fibronectin in the ECM and spread locally
4. Entrance into vascular or lymphatic spaces allows for metastasis (distant spread)
41
Routes of Metastasis
```
Carcinoma = spreads through lymphatics
Sarcomas = spreads through blood
```
Exceptions of carcinoma that spread through blood
- Renal cell carcinoma = spread through renal vein
- Hepatocellular carcinoma = invades hepatic vein
- Follicular carcinoma of thyroid
- Choriocarcinoma
42
What is the only way to make a diagnosis of cancer?
Biopsy or excision is required before a tumor can be classified as benign or malignant with certainty
43
Intermediate filaments
Differ based on cells
- used for immunohistochemistry to identify a tumor
```
Keratin = Epithelium ==> carcinoma
Vimentin = Mesenchyme ==> sarcoma
Desmin = Muscle
GFAP = neuroglia
Neurofilament = neurons
```
44
Chromogranin
Used to find small cell carcinoma or carcinoid tumors
- both derived from Neuroendocrine cells
- use with immunohistochemistry
45
S-100
Tumor marker for melanoma, schwannoma, and langerhans cell histiocytosis
46
Grading vs. Staging of Cancer
Grading = differentiation
- well differentiation cancers have better prognosis than poor
- determines prognosis
Staging = TMN = size or depth = T, metastasis, and nodal involvement
- KEY Prognostic factor; more important than grade
- metastasis is the single most important prognostic factor
47
Gastric Cancer
- more prevalent in JApan
48
Hemangioma, teratomas, fibromatoses
- common pediatric neoplasms that are benign
- Grow slowly and remain localized
- do not invade or metastasize
49
Radon Gas
- second most common cause for lung cancer that is squamous cell after smoking
- radon seeps from soil and may collect in houses
50
Flow cytometry
- detects the degree of aneuploidy from the DNA content
| - if neoplasm is aneuploidy it is more aggressive
51
Carcinoma vs. Sarcoma
Carcinoma = derived from epithelium and contain cytokeratins
Sarcoma = derived from mesenchymal cells and contain vimentin
