Pathology Flashcards
Pneumatosis intestinalis
gas cysts in the intestine wall
Toxic epidermal necrolysis
♣ Code: walls covered in rotting skin oozing green and grim reapers/toxic epidermal necrolysis. John, Canadian immunology professor/usually older. Skin looks like belwo/more severe version of Steven-Johnson syndrome. Russians drinking vodko/presentation = diffuse erythema + blistering with a positive Nikolsky sign. Lips completely necrotic and blistering/usually presents with involvement of mucous membranes. Pile of piles behind him/usually triggered by use of a new medication.
♣ Character: Room inside of SJS room
caspases
cytosolic proteases involved in apoptosis
apoptosis characteristics
- cell shrinkage + chromatin condensation + membrane blebbing + formation of apoptotic bodies, which are then phagocytosed.
- deeply eosinophilic cytoplasm + basophilic nucleus + pyknosis + karyorrhexis.
pyknosis
nuclear shrinkage
karyorrhexis
fragmentation of the nucleus caused by endonucleases cleaving at internucleosomal regions.
Indicator of apoptosis
DNA laddering
DNA laddering
(fragments in multiples of 180 bp)
differentiating feature from apoptosis and necrosis
cell membrane remains intact without significant inflammation
Pathway involved in tissue remodeling in embryogenesis
intrinsic (mitochondrial) pathway.
When does intrinsic pathway occur?
1) regulating factor is withdrawn from a proliferating cell population (decreased IL-2 after a completed immunologic regulation leading to apoptosis of proliferating effector cells).
2) after exposure to injurious stimuli (radiation, toxins, hypoxia).
Intrinsic pathway regulation and examples
Bcl-2 family of proteins, such as BAX and BAK (proapoptic) and Bcl-2 (antiapoptotic)
Bcl-2 action
Prevents cytochrome c release by binding to and inhibiting APAF-1.
APAF-1 action
APAF-1 binds cytochrome c and induces activation of caspase 9, initiating caspase casade.
What happens with Bcl-2 over expression?
decreased caspase activation and tumorigenesis.
extrinsic (death receptor) pathway
2 pathways:
1) ligand receptor interactions (FasL binding to Fas [CD95] or TNF-alpha binding to TNF)
2) Immune cell (cytotoxic T-cell release of perforin and granzyme B)
When is Fas-FasL interaction necessary? What happens with mutations?
Thymic medullary negative selection. Mutations in Fas increase numbers of circulating self-reacting lymphocytes due to failure of clonal deletion.
What happens with defective Fas-FasL interactions?
Autoimmune lymphoproliferative syndrome.
Intrinsic pathway with DNA damage/radiation/misfolded proteins/hypoxia etc.
DNA damage –> p53 activation –> BAX/BAK activation –> cytochrome C release –> initiator caspases –> executioner caspases
necrosis
Enzymatic degradation and protein denaturation of cell due to exogenous injury leading to intracellular components leak. *inflammatory process.
coagulative necrosis cause and location
ischemia/infarcts. Most tissues except brain.
What happens with coagulative necrosis
proteins denature. enzymes are degraded. cell outlines preserved. increased cytoplasmic binding of acidophilic dyes.
when does liquefactive necrosis occur?
bacterial abscesses + brain infarcts (due to icnreased fat content)
liquefactive necrosis pathophys
Neutrophils release lysosomal enzymes that digest the tissue; enzymatic degradation first, then proteins denature.
liquefactive necrosis histology
Early: cellular debris and macrophages.
Late: cystic spaces and cavitation (brain).
Neutrophils and cell debris seen with bacterial infection.
When does caseous necrosis occur?
TB + systemic fungi (histoplasma) + nocardia.
What happens with caseous necrosis?
Macrophages wall of infecting microorganism –> leading to granular debris.
Histology of caseous necrosis
Fragmented cells and debris surrounded by lymphocytes and macrophages.
pathophys of fat necrosis
damaged cells release lipase, which breaks down TGs in fat cels.
Histology of fat necrosis and appearance
Outlines of dead fat cells without peripheral nuclei; saponification of fat (combined with ca2+). Appears dark blue on H&E stain.
another example of fibrinoid necrosis
GCA
Fibrinoid necrosis pathophys
immune complexes combine with fibrin leading to vessel wall damage
fibrinoid necrosis pathophys
vessel walls thick and pink.
dry vs. wet gangrenous necrosis
Dry occurs with ischemia and presents with coagulative necrosis histologically.
Wet occurs with superinfection and presents with liquefactive superimposed on coagulative.
lysosomal rupture – reversible or irreversible sign of cell injury?
irreverisble
membrane blebbing – reversible or irreversible sign of cell injury?
reversible
cellular/mitochondrial swelling – – reversible or irreversible sign of cell injury?
reversible
nuclear pyknosis – reversible or irreversible sign of cell injury?
irreversible
karyorrhexis – reversible or irreversible sign of cell injury?
irreversible
karyolysis – reversible or irreversible sign of cell injury?
irreversible
ribosomal/polysomal detachment (decreased protein synthesis)
reversible
nuclear chromatin clumping – reversible or irreversible sign of cell injury?
reversible
decreased glycogen – reversible or irreversible sign of cell injury?
reversible
mitochondrial permeability/vacuolization – reversible or irreversible sign of cell injury?
irreversible
mitochondrial permeability/vacuolization
phospholipid-containing amorphous densities within mitochondria
plasma membrane damage mitochondrial permeability/vacuolization
irreersible
nuerons most vulnerable to hypoxic-ischemic injury
Purkinje cells of cerebellum + pyramidal cells of hippocampus and neocortex
area of heart most susceptible to ischemia
subendocardium of LV
area of kidney most susceptible to ischemia
straight segment of proximal tubule (medulla) + thick ascending limb (medulla)
red infarct
hemorrhagic infarcts that occur in venous occlusion and tissues with multiple blood supplies and with reperfusion (eg after angioplasty) (Red; reperfusion).
tissues with multiple blood supplies
liver, lung, intestine, testes.
What causes reperfusion injury?
damage by free radicals.
Pale infarcts
(anemic) infarcts. Occur in solid organs with a single (end-arterial) blood supply.
organs with a single blood supply
heart, kidney, spleen.
characteristics of inflammation
rubor (redness), dolor (pain), calor (heat), tumor (swelling), functio laesa (loss of function)
vascular component of inflammation
increased vascular permebaility + vasodilation + endothelial injury
Acute inflammation
neutrophil, eosinophil, and antibody mediated. rapid onset and short duration.
Possible outcomes of acute inflammation
Complete resolution + abscess formation OR progression to chronic.
What mediates chronic inflammation?
Mononuclear cells (monocytes/macrophages, lymphocytes, plasma cells) + fibroblasts.
chronic inflammation histoogy
Blood vessel proliferation, fibrosis.
Outcomes of granuloma formation
scarring and amyloidosis.
characteristics of chromatolysis
round cellular swelling + displacement of nucleus to the periphery + dispersion of nissl substance throughout cytoplasm
when does chromatolysis occur?
concurrent with Wallerian degeneration.
dystrophic calcification
calcium deposition in abnormal tissues secondary to injury or necrosis
dystrophic calcification characteristics
Tends to be localized, small bony tissue, and thick fibrotic wall.
When does dystrophic calcification occur?
1) TB (lungs and pericardium)
2) liquefactive necrosis of chronic abscesses
3) fat necrosis
4) infarcts
5) thrombi
6) schisto
7) Monckeberg arteriolosclerosis
8) congenital CMV
9) toxo
10) psammoma bodies
Is dystrophic calcification related to hypercalcemia?
not directly associated with hypercalcemia (patients usually normocalcemic)
calciphylaxis
rare syndrome of vascular calcification + thrombosis + skin necrosis. Usually seen in patients with stage 5 CKD. Affects 1-4% of all dialysis pts.
metastatic calcification
Widespread depositoin of calcium in normal tissue secondary to hypercalcemia. Patients usually hypercalcemic.
metastatic calcification presentation
metastatic calcifications of alveolar walls in acute pneumonitis.
Where does calcium deposit in metastatic calcification?
Interstitial tissues of kidney, lung, and gastric mucosa.
Why does metastatic calcification occur in these tissues?
These tissues lose acid quickly, and increased pH favors calcium deposition.
Where does leukocyte extravasation usually occur?
postcapillary venules
Steps of leukocyte extravasation
1) margination and rolling
2) tight-binding
3) diapedesis
4) migration
LAD type 2 defect
defective margination and rolling (decreased Sialyl-Lewis)
proteins involved in vasculature stroma of margination and rolling
1) E-selectins
2) P-selectins
3) GlyCAM-1, CD34
leukocyte protein that binds to E and P selectins
sialyl-LewisX
Leukocyte protein that binds to GlyCAM-1, CD34
L-selectin
which step is defective in LAD type 1?
Tight-binding
Proteins involved in tight binding
1) ICAM-1
2) VCAM-1
ICAM-1 cell marker
CD54
VCAM-1 cell marker
CD106
leukocyte protein that binds to ICAM-1?
CD11/18 integrins (LFA-1, Mac-1)
leukocyte protein that binds to VCAM-1?
VLA-4 integrin
Protein involved in diapedesis
PECAM-1
PECAM-1 cell marker
CD31
leukocyte protein that binds to PECAM-1?
PECAM-1
chemotactic products promoting migration…
C5a, IL-8, LTB4, kallikrein, platelet-activating factor.
How do free radicals damage cells?
Membrane lipid peroxidation, protein modification, DNA breakage.
What initiates free radical damage
Radiation, Phase 1 drug metabolism, redox reactions, NO, transition metals, WBC oxidative burst.
scavenging enzymes and examples
enzymes that eliminate free radicals. catalase, superoxide dismutase, glutathione peroxidase.
Other means of eliminating free radicals
1) spontaneous decay
2) antioxidants
3) certain metal carrier proteins (transferrin, ceruloplasmin)
antioxidant vitamins
A, C, and E
bronchopulmonary dysplasia
dysplasia due to oxygen toxicity and free radicals
Other examples of free radical demage
1) carbon tetrachloride
2) acetaminophen overdose
3) hemochromatosis
4) Wilson’s
Things that can cause inhalational injury
heart, particulates less than 1 micrometer in diameter, irritants (NH3), CO inhalation, arsenic poisoning.
Inhalational injury presentation
chemical tracheobronchitis + edema + pneumonia + ARDS
Bronchoscopy findings in inhalational injury.
Severe edema, congestion of bronchus, and soot deposition
soot deposition timeframe
18 hours after inhalation injury, resolution at 11 days after injury.
Scar formation timeline
70-80% of tensile strength regained at 3 months; little additional tensile strength regaiend afterward.
Hypertrophic scars:
1) collagen synthesis
2) collagen organization
3) extent of scar
4) scar evolution
5) recurrence
1) increased
2) parallel
3) confined to borders
4) possible spontaneous regression
5) infrequent
keloid scars
1) collagen synthesis
2) collagen organization
3) extent of scar
4) scar evolution
5) recurrence
1) increased a lot
2) disorganized
3) extends beyond borders of original wound with “clawlike” projections
4) possible progressive growth
5) frequent
* increased in dark skinned people
Tissue mediators of wound healing
1) PDGF
2) FGF
3) EGF
4) TGF-beta
5) metalloproteinases
6) VEGFg
PDGF role in wound healing
Secreted by activated platelets and macrophages.
Indcues vascular remodeling and smooth muscle migration.
Stimulates fibroblast growth for collagen synthesis.
FGF role in wound healing
Stimulates angiogenesis.
EGF role in wound healing
Stimulates cell growth via tyrosine kinases (EGFR/ErbB1)
ErbB1
tyrosine kinase
TGF-beta role in wound healing
angiogenesis + fibrosis + cell cycle arrest
metalloproteinases role in wound healing
tissue remodeling
Phases of wound healing and timeframe
1) inflammatory (up to 3 days after)
2) proliferative (day 3-weeks after wound)
3) remodeling (1 week-6+ months after wound)
Effector cells of inflammatory wound response phase
platelets, neutrophils, macrophages
Effector cells of proliferative wound response phase
fibroblasts, myofibroblasts, endothelial cells, keratinocytes, macrophages
Effector cells of remodeling wound response phase
fibroblasts
characteristics of inflammatory wound response phase
Clot formation + increased vessel permeability and neutrophil migration into tissue; macrophages clear debris 2 days later.
characteristics of proliferative wound response phase
Deposition of granulation tissue and type III collagen, angiogenesis, epithelial cell proliferation, dissolution of clot, and wound contraction
mediator of wound contraction
myofibroblasts
characteristics of remodeling wound response phase
Type III collagen replaced by Type I collagen, which functions to increase tensile strength of tissue.
bacterial causes of granulomatous diseases
1) mycobacteria (TB, leprosy)
2) bartonella henselae
3) listeria
4) tertiary syphilis
5)
Listeria infection in a newborn disease
granulomatosis infantiseptica
parasitic granulomatous disease
schistosomiasis
Fungal causes of granulomatous diseases
Fungal: endemic mycosis (histoplasmosis)
foreign material causes of granulomatous diseases
1) berylliosis
2) talcosis
3) hypersensitivity pneumonitis
autoinflammatory causes of granulomatous diseases
Sarcoidosis Crohn disease PBC Subacute (de Quervain/granulomatous) thyroiditis Wegener Churg-Strauss GCA Takayasu
TNF-alpha function in granuloma formation
INduces and maintains granuloma formation
exudate appearance
cellular, cloudy
Exudate characteristics
1) increased protein
2) increased LDH (vs serum)
3) SG>1.020
causes of exudate
1) lymphatic obstruction (chylous)
2) inflammation/infection
3) malignancy
transudate appearance
hypocellular (clear)
transudate characteristics
1) decreased protein
2) decreased LDH (vs serum)
3) SG ess than 1.012
Causes of transudate
1) increased hydrostatic pressure (eg HF, Na retention
2) decreased oncotic pressure (eg, cirrhosis, nephrotic syndrome)
ESR pathophys
products of inflammation (eg fibrinogen) coat RBCs and cause aggregation. Denser RBC aggregates fall at a faster rate in a pipette tube.
Causes of increased ESR
1) anemias
2) infections
3) inflammation (GCA, polymyalgia rheumatica)
4) cancer
5) renal disease (ESDR or nephrotic syndrome)
6) pregnancy
Causes of decreased ESR
1) sickle cell anemia (altered shape)
2) polycythemia (increased RBCs dilute aggregation factors)
3) HF
4) microcytosis
5) hypofibrinogenemia
H&E staining of amyloidosis
Shows deposits in glomerular mesangial areas and tubular basement membranes
amyloidosis pathophys
Abnormal aggregation of proteins (or fragments) into beta-pleated linear sheets causing damage and apoptosis.
AL amyloidiosis (primary) etiology
deposition of proteins from Ig Light chains
AA amyloidosis (secondary) substance
fibrils composed of serum AMyloid A
Examples of AA amyloidosis
1) RA
2) IBD
3) spondyloarthropathy
4) familial Mediterranean fever
5) protracted infection
dialysis amyloidosis
fibrils composed of beta2-microglobulin
Heritable amyloidosis
heterogeneous group of disorders, including familial amyloid polyneuropathies due to transthyretin gene mutation.
amyloid deposited in age-related amyoidosis + location + features
normal (wild-type) transthyretin (TTR). Cardiac ventricles. Slower progression than primary.
amyloid type in AD
beta-amyloid cleaved from amyloid precursor protein.
amyloid type in DM2 + etiology
Islet amyloid polypeptide (IAPP). Caused by deposition of amylin in pancreatic islets.
Isolated atrial amyloidosis
Due to ANP. Common in normal aging.
atrophy
decrease in tissue mass due to decrease in size and/or number of cells.
causes of atrophy
1) disuse
2) denervation
3) loss of blood supply
4) loss of hormonal stimulation
5) poor nutrition
Is hyperplasia premalignant?
Can be an RF for future malignancy but not considered premalignant.
Is dysplasia reversible?
Only refers to epithelial cells. Mild dysplasia is usually reversible; severe dysplasia usually progresses to carcinoma in situ.
Well-differentiated vs. poorly-differentiated
Well-differentiated tumors closely resemble their tissue of origin; poorly differentiated look almost nothing like their tissue of origin.
Anaplasia
complete lack of differentiation of cells in a malignant neoplasm
hallmarks of cancer
1) evasion of apoptosis
2) growth signal self-sufficiency
3) anti-growth signal insensitivity
4) sustained angiogenesis
5) limitless replicative potential
6) tissue invasion
7) metastasis
dysplasia
Proliferation of cells with loss of size, shape, and orientation.
Carcinoma in situ characteristics
1) no BM invasion
2) increased N/C ratio
3) clumped chromatin
4) neoplastic cells encompass entire thickness.
invasive carcinoma etiology
1) Cells invade BM using collagenases and hydrolases (metalloproteinases).
2) Cell-cell contacts lost by inactivation of E-cadherin.
Seed and soil theory of metastasis
Seed = tumor embolus Soil = target organ, often first-encountered capillary bed
Low grade
Well-differentiated
high grade
poorly differentiated, undifferentiated, or anaplastic
Most important of TNM for staging?
1) Each TNM factor has independent prognostic value.
2) M factor often most impt.
carcinoma
epithelial origin
sarcoma
mesenchymal origin
choristoma
normal tissue in a foreign location (eg gastric tissue in distal ileum in Meckels).
tumor of connective tissue
fibroma
skin cancer epidemiology
basal>squamous»melanoma
Most common cancer
Skin cancer
lung cancer epidemiology historically
Incidence has dropped in men, but hasn’t changed significantly in women.
Top 3 cancers in men, incidence
1) prostate
2) lung
3) colorectal
Top 3 cancers in women, incidence
1) breast
2) lung
3) colorectal
Top 3 cancers in men, mortality
1) lung
2) prostate
3) colorectal
Top 3 cancers in women, mortality
1) lung
2) breast
3) colorectal
Top 2 leading causes of death in US
1) cardiovascular 2) cancer
PTHrP/hypercalcemia seen in
1) SCC of lung, head, and neck
2) renal
3) bladder
4) breast
5) ovarian
6) lymphoma
paraneoplastic polycythemia seen in
1) RCC
2) HCC
3) hemangioblstoma
4) pheochromocytoma
5) leiomyoma
Pure red cell aplasia
anemia with low reticulocytes, paraneoplastic syndrome
Pure red cell aplasia associated cancer
Thymoma
Good syndrome
paraneoplastic hypogammaglobulinemia
Good syndrome associated cancer
Thymoma
nonbacterial thrombotic (marantic) endocarditis
Deposition of sterile platelet thrombi on heart valves
nonbacterial thrombotic (marantic) endocarditis associated with
pancreatic adenocarcinoma
Anti-NMDA receptor encephalitis presentation
psychatric disturbance + memory deficits + seizures + dyskinesias + ANS instability + language dysfunction
Anti-NMDA receptor encephalitis association
ovarian teratoma
opsoclonus-myoclonus ataxia syndrome presentation
“dancing eyes, dancing feet”
opsoclonus-myoclonus ataxia syndrome association
children –> neuroblastoma
adults –> small cell lung cancer
paraneoplastic cerebellar degeneration
antibodies against Hu, Yo, and Tr antigens in purkinje cells
paraneoplastic cerebellar degeneration associations
Small cell lung cancer, gynecologic and breast cancer, Hodgkin lymphoma
paraneopalstic encephalomyelitis etiology
antibodies against HU antigens in neurons
paraneopalstic encephalomyelitis etiology
small cell lung cancer
ALK gene product
RECEPTOR tyrosine kinase (oncogene)
BCR-ABL gene product
NONreceptor tyrosine kinase
BCR-ABL association
CML, ALL
BRAF gene product
serine/threonine kinase
BRAF association
Melanoma + non-Hodgkin lymphoma
c-KIT gene product
cytokine receptor
HER2/neu (c-erbB2) gene product
tyrosine kinase
HER2/neu (c-erbB2) association
breast and gastric carcinomas
JAK2 association
chronic myeloproliferative disorders
KRAS gene product
GTPase
KRAS association
colon cancer, lung cancer, pancreatic cancer
MYCL1 gene product
transcription factor
RET associated with
MEN 2A,2B + medullary thyroid cancer
CDKN2A association
melanoma + pancreatic cancer
CDKN2A gene product
p16, blocks G1–> S phase
DPC4/SMAD4 association
pancreatic cancer (deleted in pancreatic cancer)
MEN1 gene product
Menin
NF1 gene product
Ras GTPase activating protein (neurofibromin)
NF2 gene product
Merlin (schwannomin) protein
PTEN + association
Tumor suppressor gene associated with breast + prostate + endometrial cancer
Rb gene product
Inhibits E2F; blocks G1–> S phase
TP53 gene product
p53, activates p21, blocks G1-S phase
TSC1 gene product
hamartin protein
TSC2 gene product
tuberin protein
VHL gene product
inhibits hypoxia inducible factor 1a
another name for Wilms tumor
nephroblastoma
EBV associated cancers
Burkitts
Hogkins
Nasopharyngeal
Primary CNS lymphoma
HBV, HCV cancer association
HCC + lymphoma
HPV cancer association
cervical and penile/anal carcinoma, head and neck cancer.
H pylori cancer association
Gastric adenocarcinoma + MALT lymphoma
alkylating agents are carcinogenic to…
blood, leukemia/lymphoma
benzidine
aromatic amine, bladder carcinogen
arsenic carcinogenic to
Angiosarcoma
Lung cancer
squamous cell carcinoma
carbon tetrachloride –> 1) organ affected 2) impact
1) liver
2) centrilobular necrosis, fatty change
ethanol carcinogenic
esophageal squamous cell carcinoma
HCC
2nd leading cause of lung cancer after cigarette smoke
lung cancer
psammoma bodies
laminated, concentric spherules with dystrophic calcification
psammoma bodies seen in
1) papillary carcinoma of thyroid
2) serous papillary cystadenocarcinoma of ovary
3) meningioma
4) malignant mesothelioma
Are tumor markers used for diagnosis or screening?
Shouldn’t be used as primary tool for diagnosis or screening. May be used to monitor recurrence and resposne to therapy, but need biopsy for definitive diagnosis.
ALP as a tumor marker
Pagets, seminoma, or *mets to bone or liver.
alpha-fetoprotein associations
HCC
*hepatoblastoma
yolk sac (endodermal sinus) tumor
*mixed germ cell tumor
high levels of alpha-fetoprotein associated with..
NTDs + *abdominal wall defects
what produces beta-HCG?
Syncytiotrophoblasts of the placenta
Beta-HCG as a tumor morker
1) hydatidiform moles and choriocarcinomas
2) testicular cancer
3) mixed germ cell tumor
CA 15-3/CA 27-29
breast cancer
calcitonin as a tumor marker
Medulary thyroid carcinoma
CEA as a tumor marker
Very nonspecific. Produced by 70% of colorectal and pancreatic cancers; also produced by gastric, breast, and medullary thyroid carcinomas.
PSA elevated in…
BPH, prostatitis, prostate cancer.
PSA useful for screening?
Questionable risk/benefit for screening given that it’s elevated in other conditions
P-glycoprotein
AKA multidrug resistance protein 1 (MDR1). Used to pump out toxins, including chemotherapeutic agents (one mechanism of decreased responsiveness or resistance to chemo over time).
P-glycoprotein cancer associations
Adrenal cell carcinoma classically, but also colon, liver.
Cachexia mediators
TNF + IFN-gamma + IL-1 + IL-6
General rule of thing about mets
Most sarcomas spread hematogenously; most carcinomas spread via lymphatics.
Exceptions to general rule about carcinoma mets
HCC, RCC, follicular thyroid carcinoma, choriocarcinoma.
Most common mets to brain
Lung, breast, prostate, melanoma, GI
Brain tumors
50% are from mets
Most common mets to liver
colon, stomach, pancreas
Most common mets to bone
prostate/bresat, lung,thyroid,kidney
Most common sites of mets in general
(after regional lymph nodes) liver and lung
caveats at bone mets
1) bone mets are a lot more common than primary bcone tumors
2) mets have a predilection for axial skeleton
Breast to bone mets pattern
mix of lytic and blastic
lung to bone mets pattern
mix of lytic and blastic
thyroid to bone mets pattern
lytic
kidney to bone mets pattern
lytic
prostate to bone mets pattern
blastic
