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adaptive changes:
fatty change, hydropic chage (early reversible injury)
atrophy, hyperplasia, hypertrophy, metaplasia (persistent injury)

Dysplasia: an irregular alteration in size, shape, and organization of 
cells in a tissue. it often occurs in areas of hyperplasia and 
metaplasia. IMPORTANTLY, dysplasia shares cytologic features with cancer 
and is considered a PRENEOPLASTIC change.  It's not really an adaptive 
cells. these cells have started to lose normal cell cycle control. these 
cells start to look like tumor cells. often occurs in situations of 
chronic injury, chronic stress. do NOT confuse this with organ dysplasia. 
organ dysplasia is when normal units of organ don't form - eg, renal 
dysplasia, nephrons are abnormal. that's CONGENITAL.

also - hypoplasia is congenital decrease in normal size. atrophy implies 
it was at one time normal, and is now smaller.

Neoplasia: cells get out of control. cells more primitive, not well 
differentiated.

slides: normal and dysplastic skin. normal: basal layer has dark nuclei. 
cells get more differentiated toward the surface. they get flat, paler, 
squamous cells. dysplastic: basal cells have large nuclei, cells are not 
relating in normal manner. mitosis is occuring in layers closer to the 
surface. there is pleomorphism (cells are different sizes), karyomegaly 
(big nuclei), cells not maturing at normal rate, etc. these are all 
features of neoplasia

remember - metaplasia is change from one normal cell type to another 
normal cell type. has no features of neoplasia.

CELL DEATH:
result of irreversible injury: cell unable to adapt.
the mechanism leading to the POINT OF NO RETURN is unknown
cellular events are similar to those discussed with cell injury: hypoxia, 
decreases in ATP, pH, protein, and RNA synthesis, plasma membrane 
dysfunction, increase in degradative enzymes, calcium influx.

NECROSIS: death of cells in a living organism. when tissue is reemoved 
from organism, cells die, but do not become necrotic. in living thing, 
the cells that die take on characteristic appearance grossly and on histo 
that we recognize as death.
is the sum of all morphologic changes folowing cell death in living 
tissue/organs. characteristic changes to cells underegoing necrosis used 
to identify them: nuclear changes eg pyknosis, karyolysis, karyorrhexis; 
and cytoplasmic changes eg eosinophilia. the nucleus condenses, gets 
smaller, stains blue/black - that's pyknosis. if there are enzymes around 
or if the cell has time to undergo enzymatic digestion, we may see 
karyolysis or karyorrhexis of the nucleus as well. cytoplasm undergoes 
condensation as well, cell shrinks, so more protein in smaller area, so 
is more eosinophilic. so cells are shrunken with pyknotic dark or lysed 
nucleus, and pink cytoplasm.

karyolysis: only a vague outline of the nucleus is left
karyorrhexis: chromatin is condensed, then starts breaking into big blue 
chunks.
you see it only as "nuclear debris"

slide: cellular death in nervous system. a few cells are a darker pink, 
and have very dark, smaller nuclei. this is coagulation necrosis and it 
DOES SO HAPPEN in the brain. don't believe the hype about it not 
happening in the brain. you can still make out the cell form and nucleus, 
so it is not liquefactive necrosis.

necrosis is always acute. 
slide: dog liver - acute necrosis with karyorrhexis and karyolysis.

we're talking about "coagulation necrosis" type necrosis right now.

AUTOLYSIS: self digestion
it's a process of autodegradation of a cell by its lysosomes. it happens 
to us all when we die. occurs in ALL CELLS when an organism dies. should 
not be confused with necrosis. is loss of normal controls, 
checks/balances - enzymes ooze out of lysosomes, etc. the longer an 
animal is dead, the more advanced the cellular degradation becomes. 
grossly, you see autolysis because putrefactive bacteria is growing and 
producing enzymes that lyse cells. animals get bloated, and they smell. 
there are color changes, tissue changes.

slide: autolysed dog liver. can see central vein, remnant of bile duct. 
hepatocytes are all disrupted - all decayed, can't tell if there was ever 
any necrosis. everything is the same color b/c autolytic enzymes degraded 
all the proteins.

slide: small intestine undergoing autolysis. can't tell what the heck it 
is.

don't leave animals lying around if you're going to do a necropsy! 
refrigerate them RIGHT AWAY to decrease enzymatic activity and bacterial 
enzyme activity. this will slow (not stop) the decay process.

GI tract one of first things to decay. if you're worried about getting GI 
tissue study, need to take sample IMMEDIATELY after death, ifnot before. 
gall bladder also, because it will autodigest really fast.
 
classic morphological patterns of tissue necrosis:  remember that in 
necrosis, you see normal cells around the dead cells. with autolysis, 
everything is falling apart.
dissolution of dead cells may follow different pathways depending on 
amount of proteolysis. 
rate and amt of proteolysis deteremines appearance of necrotic tissues
patterns of necrosis often suggest the inciting cause of cell death
the classic patterns tend to be suggestive of particular disease states.
classic patterns include: 

-coagulative necrosis: already discussed. "tombstone" cells, associated 
with sudden ischemia. pattern due to protein denaturation in absence of 
degradation by inflammatory cells. inflammatory cells can't get there due 
to lack of blood supply! heart and kidney commonly affected. THE MOST 
COMMON CAUSE OF COAGULATION NECROSIS IS ISCHEMIA/INFARCT/LACK OF BLOOD. 
grossly, affected area is lighter than surrounding tissue. over time, 
with reperfusion, we would see lysis and removal of damaged cells. in 
general most organs are mahogany due to blood. when cells die, they look 
light tan or paler than surrounding tissue.

slide: kidney. arcuate artery was blocked. affected tissue more glassy 
pink with some very dark areas, as contrasted to a less even, slightly 
less bright pink of normal tissue. affected area surrounded by rim of 
hemorrhage. close up shows cells with pyknotic nuclie or karyolysis, 
karyorrhexis. clearly coagulative type because can see normal 
architecture. grossly there is are multifocal wedge shaped tan lesions 
consistent with acute coagulation necrosis.
"white infarct" - didn't get reperfused.

slide: kidney with red wedge (infarct). there was reperfusion and massive 
hemorrhage at area of infarct - "red infarct". also there is evidence of 
chronic fibrosis in other areas - looks like it's had prior infarcts.

remember, whenever a tissue is damaged and cells can't regenerate, 
fibrosis will occur. in liver, hepatocytes can regenerate. but in kidney, 
nephrons can't regenerate. also, if you disrupt the stroma of the liver, 
will become fibrotic.
necrosis, hemorrhage == acute
fibrosis, contracture == chronic.

the kidney described above had chronic, active infarcts of the kidney.
when we start seeing some contracture, we can say it's subacute to 
chronic.

realize that chemicals can cause coagulation necrosis as well. cyanide 
will stop the e- transport chain so could cause this. also monensin - a 
coccidiostat used in chickens also used as growth stimulant in cattle. if 
horses get monensin they have problems. it is an ionophore - binds ions 
and moves them across membranes. it brings Na+ into cells, disrupting 
normal pH and depolarization of cell. if it happens in lg amt, you see 
coagulation necrosis. in 1989 monensin got into horse feed in NJ. many 
horses died. those that survived stayed at NBC for research. heart tissue 
of dead horses examined histologically showed: vague outlines of 
myocardiocytes, clusters of pyknotic nuclei, mineralization of myocytes. 
that looks dark red histologically, chalky white grossly.

slide: white muscle disease of lamb. muscle is very pale tan compared to 
normal muscle. in this case, free radicals caused coagulation necrosis.

most COMMON CAUSE of coag. nec. is ISCHEMIA. 
very little proteolytic digestion of area occurs in coagulation necrosis.

slide: 
normal myocardium
coagulative necrosis affecting myocardiocytes. can see cell outlines and 
dark inside cell. surrounded by normal tissue.
liquefactive necrosis affecting myocardiocytes. neutrophils have 
infiltrated and destroyed the myocardiocytes in the region. total 
disruption of normal architechture. no "ghost cells" left. pus present.


slide: heart with irregular light tan area around coronary artery. 
probably coag necrosis from ischemia. multifocal, acute necrosis.

slide: liver from puppy with herpesvirus. although liver is affected all 
over, this is a multifocal pattern. entire liver has multifocal to 
coalesching pinpoint to 3 mm white foci. moderate to severe multifocal 
acute heptic necrosis.

note that it is hard to cause infarct in liver due to dual blood supply.

-liquefactive necrosis: very liquidy, pus. complete destruction of the 
dead cells in an affected area with loss of architechture. when you cut 
into area, stuff flows out. neutrophils have destroyed tissue and also 
they become part of pus. only nuclear and cytoplasmic debris remain. due 
to potent hydrolases released by neutrophils, which are also destroyed. 
typically associated with bacterial infections. pus, abscess. if you look 
only at a region of liquefactive necrosis, you can't tell what tissue it 
is from. 99.9% of cases are caused by bacteria. why is pus green? because 
neutrophils contain metalloproteases which require a metal, the most 
commonly used being iron. when they are oxidized, they turn green. a 
collection of neutrophils in a tissue which forms a pocket of pus is 
called an abscess. now, even though necrosis is acute, some abscesses are 
chronic. an inciting agent caused neuts to get there, but then body also 
tried to wall off the area - and it gets walled off with fibrous CT. then 
the abscess remains, sitting there, filled with pus, walld off by thick 
wall of fibrous CT. that's a chronic process. reptiles and birds form 
abscesses very quickly. also they form granulomas quickly. because they 
don't have very effective neutrophils for digesting bacteria. so they 
wall off the area pretty fast. 

slide: cow brain affected with listeria. looks like big'ol pile of purple 
dots. this is a microabscess, because they had to find it histologically. 
a sea of neuts has destroyed the parenchyma and also themselves. can see 
a mat of bacteria present as well. at high mag we see pyknosis, 
karyolysis, karyorrhexis, lots of debris all over the place.so even in 
liquefactive necrosis you can see these signs.

slide: pig abscess. extremely foul and disgusting. subcutaneous 
liquefactive necrosis.

slide: pus pouring out of sinuses bilaterally. severe, suppurative 
sinusitis.

never describe something as pussy because you can't write that down. 
that's why people say purulent and suppurative. but people always try to 
say pussy.

slide: kidney with liquefactive necrosis. severe, focal, acute, 
suppurative, pyelonephritis with bacteria present.

BACTERIA ARE NUMBER ONE CAUSE OF LIQUEFACTIVE NECROSIS. grossly fluid 
appearance. books say that only necrosis occuring in brain is 
liquefactive necrosis. that's not true. coagulation necrosis does occur, 
but it's very transient.brain doesn't have fibroblasts, can't repair 
itself, so if area of brain is lost for some reason, it will generally 
end up forming a cyst.

slide: spinal cord showing liquefactive necrosis - loss of architecture - 
but not pus. pus not always a feature of this process.

slide: spaces present within areas of normal parenchyma. this is 
liquefactive necrosis. there is no liquid. there are a few fibrillary 
astrocytes hanging around.


-caseous necrosis: cheese like
this occurs in tuberculosis. also in many animal diseases. well 
demarcated nodules which consist of a central area of amorphous necrotic 
debris surrounded by a wall usuallymade up of granulomatous inflammatory 
cells. is most useful as a gross description due to dry, cheesy 
appearance.
could be used to describe a dehydrated abscess, or can be result of 
granulomatous inflammation, a chronic inflammation resulting from foreign 
material like pellets or plant or fungus material, or a response to 
intracellular parasites like TB - a gram neg acid fast rod that lives in 
cytoplasm of macrophages. this form of necrosis is common in reptiles and 
birds.
as a result of TB living in macrophages, body can't get rid of the 
organism, so body tries to wall off the area where they're clustered.

slide: liver from a monkey with TB. multifocal to coalescing tan nodules 
throughout liver. feel quite firm. 

slide: from fish. histologically there is a thick wall of fibrous CT and 
epithelioid macrophages around a central area of debris. this represents 
a chronic process. epithelioid macrophages are components of granulomas. 
there are mycobacteria present in the debris.

slide: ovine LNs affected by corynebacterium.gland appears laminated and 
cracking.

remember to use caseous necrosis as a gross descriptor, and that it can 
represent a couple of dz processes.

-fat necrosis: necrosis of fat. affects adipose tissue. FFA are 
precipitateed as calcium sopas - saponification. mineral comes in and 
binds to it making it look chalky and white. this is due to phospholipase 
and protease attack of the adipocyte membrane thereby releasing 
triglycerides which are hydrolyzed to FFA. it is most commonly associated 
with trauma or pancreatic necrosis (enzymatic).
most common cause of fat necrosis we'll see is pancreatic - caused by 
release of enzymes into surrounding tissue which is generally fatty. we 
see liquefactive and coagulation necrosis and saponification.can't miss 
this. can still see outline of adipocytes, and see that there is a 
neutrophilic infiltrate, and there is mineral deposit. mineralization, 
coagulation necrosis and liquefactive necrosis all seen. this can be 
acute or ongoing. some areas can be walled off. grossly, you can see 
embedded in fat little round white foci of chalky looking material - this 
is fat necrosis with mineralization. if you see this in surgery, get out 
of there. don't move the pancreas around - that makes it worse. these 
nodules may be slightly firm, but are really kind of hard to 
differentiate from surrounding tissue. 
in subq tissue, from trauma, or from systemic necrosis secondary to 
pancreatitis that's out of control...
fat necrosis in abdomen usually due to pancreatitis.
 
-gangreneous necrosis: primarily a clinically descriptive term. first 
used to describe a gross change in people with diabetes. when people 
mention gangrene, they usuallymean an extremity that's dying on the 
person, getting withered, crunchy, and black. usually an extensive, but 
well demarcated area (distal extremity) that has undergone ischemia with 
varying degrees of coauglation or liquefactive necrosis. there is dry 
(primarily coagulative), wet (primarily liquefactive), and gas (gas 
bubbles form, crepitus present) gangrene. gas is formed by putrefactive 
bacteria.. .
black leg cuased by clostridum chauvoei in cattle, emus, and ostriches. 
causes leg to turn black due to toxins. 

APOPTOSIS:
programmed cell death. cell death in a normal tissue.
no inflammation
first described about 100yrs ago by german anatomist looking at 
regression of ovarian follicles. how/why do they regress? loss of 
hormonal stimulation, so partly due to atrophy. but atrophy is due to 
apoptosis - programmed cell death, or cell suicide. this occurs daily as 
part of normal homeostasis. hypertrophy, atrophy, and apoptosis occur to 
allow us to resculpt organs and allow regression of unneeded tissue eg 
mammary regression after weaning. normal physiologic mechanism of cell 
removal, turnover, atrophy. may also be induced by toxins, irradiation, 
viruses, and corticosteroids. as cell destroys itself, it makes little 
packages of organelles. apoptotic blebs - contain pieces of nucleus, or 
mitochondria, etc. daily, a small percentage of hepatocytes, epi cells, 
etc, undergo apoptosis for normal reasons. when looking at a molecular 
level, we found you could predict which cells would undergo it, and that 
apoptosis is a big player in alzheimers dz, some viral diseases, etc. so 
other things can induce apoptosis. P53- tumor supressor. normal cell 
protein which prevents "out of control" replication. if P53 is 
dysfunction, cell may replicate out of control. as we age, our thymus 
involutes. that happens via atrophy and apoptosis. thymocytes commit 
suicide. but, in young animal with systemic illness/stress/starvation, 
the cortisol level goes up secondary to catecholamine release, and the 
steroids bind somethign on lymphocyte and thymocyte cells, causing 
apoptosis of thymocytes. 

MINERALIZATION: deposition of calcium salts in tissues eg tissue 
calcification. 
two general categories based on serum calcium level.
DYSTROPHIC: when serum calcium is a normal level and you find 
calcification grossly and histologically, you can be sure that it has 
occured in an area of necrosis. occurs secondary to cellular changes of 
necrosis.
METASTATIC: if mineralization occurs in tissue due to very high calcium 
or phosphorus, that's abnormal. hypercalcemia is not normal. theere is 
too much ionized Ca++ floating around. there are sites all over the body 
which can bind Ca++ under these conditions. this is metastatic 
calcification. this animal had abnormal calcium homeostasis. doesn't 
occur in area of necrosis. occurs in viable tissue.
remember that calcium and phosphorus levels are tied to each other.

why does calcium bind in either condition? there are sites for the 
calcium to bind. in situations of necrosis, there has been membrane and 
protein disruption which created new binding sites. that's why calcium 
binds! in cytoplasm, there's hardly any Ca++, so when it gets in there, 
it binds anythign it can...

in metastatic calcification, we get Ca++ binding due to sheer 
overwhelming amt of calcium which will bind to anythign it can. there are 
some preferential sites in the body where it binds: under the tongue, 
because there is damage to the tongue and it opens binding sites. this 
occurs in renal failure which damages tongue due to increased acidity of 
saliva in renal failure, and puts calcium/phosphorus balance out of 
whack. also along the intercostal muscles in the thorax. we don't know 
why. lungs are prone to it, and left endocardium. don't know why. 
finally, stomach wall prone to calcification.

poorly understood idiopathic mineralization: calcinosis cutis, maybe due 
to binding sites becoming available in collagen due to 
hyperadrenocorticism. calcinosis circumscripta also in animals with 
normal serum calcium. 

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