Generalized Pathology Flashcards
Intrinsic Mitochondrial Apoptosis Pathway
- occurs after a regulating factor is withdrawn from cell population, exposure to injurious stimuli (DNA damage = radiation, toxins, free radicals, hypoxia), protein misfolding (ER stress)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
Extrinsic Death Receptor Apoptotic Pathway
- 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
Characteristics of Apoptosis
- deeply eosinophilic cytoplasm = pink cytoplasm
- cell shrinkage
- nuclear shrinkage (pyknosis)
- basophilia
- membrane blebbing
- nuclear fragmentation (karyorrhexis)
- Formation of apoptotic body that is phagocytosis
Necrosis
- 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
Coagulative Necrosis
- 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
Liquefactive Necrosis
- 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
Caseous Necrosis
- 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
Fat Necrosis
- 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
Fibrinoid Necrosis
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
Gangrenous Necrosis
- distal extremity after chronic ischemia
- Dry = ischemia ==> coagulative
- Wet = superinfection of dead ischemic tissue ==> liquefactive
Apoptosis vs. Necrosis
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
Chromatolysis
- 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
Pathological Calcifications
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
Leukocyte Extravasation
- occurs at post capillary venues
- margination and rolling, tight binding, diapedesis, and migration
Scar Formation
- 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.
Exudate vs. Transudate
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
Amyloidosis
- 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)
Lipofuscin
- 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
P-glycoprotein
- 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
Plasia’s
- dysplasia, hyperplasia, and meta plasia = reversible
- anaplasia, neoplasia, and desmoplasia = irreversible
- desmoplasia = fibrous tissue formation in response to neoplasm
Tumor Nomenclature
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
Common metastases
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
Meta plasia
- 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
Carbon Monoxide Poisoning
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
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
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
Cell death
Hallmark = loss of the nucleus
- nuclear condensation (pyknosis)
- fragmentation (karyorrhexis)
- dissolution (karyolysis)
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
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
Alfatoxin
- from aspergillus that can contaminate stored rice and grains
- causes Hepatocellular carcinoma
Arsenic
- from cigarette smoke
- causes squamous cell cancer of skin, lung, cancer, and angiosarcoma of liver
Nitrosamines
- found in smoked foods and is responsible for high rates of stomach cancer in Japan
- associated with intestinal type of stomach cancer
Napthylamine
- from cigarrette smoke
- urothelial carcinoma of bladder
Vinyl Chloride
- occupational exposure used to make polyvinyl chloride for use in pipes
- causes angiosarcoma of liver
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
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
Categories of OncogenEs
- Growth Factor
- Growth Factor receptors
- Signal Transducers
- Nuclear regulators
- Cell cycle regulators
READ PAGE 26 on PATHOMA
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
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
Tumor Invasion and Spread
- Tumor cell down regulates E-Catherine
- The tumor cell attaches to laminitis and destroys basement membrane type 4 collagen via collagense
- Tumor cell attaches to fibronectin in the ECM and spread locally
- Entrance into vascular or lymphatic spaces allows for metastasis (distant spread)
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
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
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
Chromogranin
Used to find small cell carcinoma or carcinoid tumors
- both derived from Neuroendocrine cells
- use with immunohistochemistry
S-100
Tumor marker for melanoma, schwannoma, and langerhans cell histiocytosis
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
Gastric Cancer
- more prevalent in JApan
Hemangioma, teratomas, fibromatoses
- common pediatric neoplasms that are benign
- Grow slowly and remain localized
- do not invade or metastasize
Radon Gas
- second most common cause for lung cancer that is squamous cell after smoking
- radon seeps from soil and may collect in houses
Flow cytometry
- detects the degree of aneuploidy from the DNA content
- if neoplasm is aneuploidy it is more aggressive
Carcinoma vs. Sarcoma
Carcinoma = derived from epithelium and contain cytokeratins
Sarcoma = derived from mesenchymal cells and contain vimentin
