ROBBIN’S AND COTRAN’S : PATHOLOGIC BASIS OF DISEASE

MORPHOLOGY

CELLULAR RESPONSE TO STRESS AND TOXIC INSULTS: ADAPTATION, INJURY AND DEATH
Cellular − First manifestation of almost all forms of injury to cells
Swelling − It is a difficult morphologic change to appreciate with light microscope
− It may be more apparent at the level of the whole organ
− When it affect many cells, it causes some pallor, increased turgor, and increase in
the weight of the organ
− Small clear vacuoles may be seen within the cytoplasm, these represent distended
and pinched-off segments of the ER
− Also called hydropic change or vacuolar degeneration
− Swelling of cells is reversible
− Also show increased eosinophilic staining, which becomes more pronounced with
progression to necrosis
Ultrastructural Changes:
1. Plasma Membrane Alteration-blebbing, blunting, loss of microvilli
2. Mitochondrial Changes- swelling and appearance of amorphous densities
3. Dilation of ER with detachment of polysomes- intracytoplasmic myelin figures
present
4. Nuclear alterations- disaggregation of granular and fibrillar elements

Necrotic Cells − Increased eosinophilia in HE stain due to the loss of cytoplasmic RNA and
denatured cytoplasmic protein
− May have more glassy homogenous appearance than do normal cells, mainly as a
result of loss of the glycogen particles
− When enzymes have digested the cytoplasmic organelles, the cytoplasm become
vacuolated and appears moth-eaten
− Dead cells may be replaced by large whorled phospholipid masses called myelin
figures that are derived from damaged cell membranes
− These phospholipid precipitates are then either phagocytosed by other cells or
further degraded into fatty acids
− Calcification of such fatty acid residues result in the generation of calcium soaps
− The dead cells may ultimately become calcified
− EM, necrotic cells are characterized by discontinuities in plasma and organelle
membranes, marked dilation of mitochondria with the appearance of large
amorphous densities, intracytoplasmic myelin figures, amorphous debris, and
aggregates of fluffy material probably representing denatured protein
Nuclear Changes
1. Karyolysis- basophilia of the chromatin may fade, a change that presumably
reflects loss of DNA because of enzymatic degradation by endonucleases
2. Pyknosis- nuclear shrinkage and increased basophilia, chromatin condenses into
a solid, shrunken basophilic mass
3. Karyorrhexis- pyknotic nucleus undergoes fragmentation
Coagulative − Architecture of dead tissues is preserved for a span of at least some days
Necrosis − The affected tissue exhibit a firm texture
− The injury denatures not only structural proteins but also enzymes and so block the
proteolysis of the dead cell
− Eosinophilic, anucleate cells may persist for days or weeks
− Necrotic cells are removed by phagocytosis of the cellular debris by infiltrating
leukocytes and by digestion of the dead cells by the action of lysosomal enzymes
of the leukocytes
− Ischemia caused by obstruction in a vessel may lead to coagulative necrosis of the
supplied tissue in all organs except the brain
− A localized area of coagulative necrosis is called an infarct

Liquefactive − Characterized by digestion of the dead cell

Necrosis − Transformation of the tissue into a liquid viscous mass
− It is seen in focal bacterial or, occasionally, fungal infections, because the microbes
stimulate the accumulation of leukocytes and the liberation of enzymes from these
cells
− The necrotic material is frequently creamy yellow because of the presence of dead
leukocytes and is called pus
− Hypoxic death of cells within the CNS
Gangrenous − Not a specific pattern of cell death
necrosis − Usually applied to a limb, generally the lower leg, that has lost its blood supply and
has undergone necrosis involving multiple tissue planes
− When bacterial infection is superimposed there is more liquefactive necrosis
because of the actions of degradative enzymes in the bacteria and the attracted
leukocytes
− Wet gangrene
Caseous − Most often in foci of tuberculous infection
Necrosis − Derived from a friable white mass of the area of
necrosis
− The necrotic area appears as a structureless
collection of fragmented or lysed cells and
amorphous granular debris enclosed within a
distinctive inflammatory border—granuloma

Fat necrosis − Focal area of fat destruction, typically resulting from release of activated pancreatic
lipases into the substance of the pancreas and the peritoneal cavity
− This occurs in pancreatitis
− Pancreatic enzymes leak out of acinar cells and liquefy the membranes of fat cells
in the peritoneum
− The released lipases split the triglyceride esters contained within fat cells
− The fatty acids, combine with calcium to produce grossly visible chalky-white areas
of fat saponification
 − The necrosis takes the form of foci of shadowy outlines of necrotic fat cells, with
basophilic calcium deposits surrounded by inflammatory reaction
Fibrinoid − Necrosis usually seen in immune reaction
Necrosis involving blood vessels
− Typically occurs when complexes of antigens and
antibodies are deposited in the walls of arteries
− Deposits together with fibrin that has leaked out of
vessels, result in a bright pink and amorphous
appearance in HE stain
− Immune mediated vasculitis syndrome

Apoptotic Cell 1. Cell Shrinkage- the cell is smaller in size, the cytoplasm is dense, and the
organelles, are more tightly packed
2. Chromatin Condensation- most characteristic feature of apoptosis, the chromatin
aggregates peripherally, under the nuclear membrane, into dense masses of
various shapes and sizes. The nucleus may break up producing more fragments
3. Formation of Cytoplasmic Blebs and Apoptotic Bodies
4. Phagocytosis of apoptotic cells or cell bodies by macrophages
− Plasma membrane are thought to remain intact during apoptosis, until the last
stages, when they become permeable to normally retained solutes
− Appear as a round or oval mass of intensely eosinophilic cytoplasm with fragments
of dense nuclear chromatin

Calcification Calcium salts have a basophilic, amorphous granular, sometimes clumped

−
appearance
− They can be intracellular, extracellular or in both locations
− Heterotopic bone may be formed in the focus of calcification
− Single necrotic cells may constitute seed crystal that become encrusted by mineral
deposits
− The progressive acquisition of outer layers may create lamellated configurations,
called psammoma bodies because of their resemblance to grains of sands
− Some types of papillary cancers (thyroid) are apt to develop psammoma bodies
− In asbestosis, calcium and iron salts gather about long slender spicules of
asbestosis in the lung, creating exotic, beaded dumbbell forms
INFLAMMATION AND REPAIR
Granulomatous − Activated macrophages in granulomas have pink granular cytoplasm with distinct
Inflammation cell boundaries called epithelioid cells because of their resemblance to epithelia
− The aggregates of epithelioid macrophages are surrounded by collar of
lymphocytes
− Older granuloma may have a rim of fibroblasts and connective tissue
− Multinucleated giant cells 40 to 50 um in diameter are found in granulomas-
 Langhans giant cell
They consist of a large mass of cytoplasm and many nuclei, and they derive from
−
the fusion of multiple activated macrophages
− Mtb- a combination of hypoxia and free-radical mediated injury leads to a central
zone of necrosis, grossly, this has a granular, cheesy appearance and is therefore
called caseous necrosis
− Microscopic, this necrotic material appears as a amorphous, structureless,
eosinophilic, granular debris, with complete loss of cellular details
− Noncaseating granuloma- Crohn disease, sarcoidosis, foreign body reaction
HEMODYNAMIC DISORDERS, THROMBOEMBOLIC DISEASE, AND SHOCK
Edema − Recognized grossly
− Appreciated as clearing and separation of the extracellular matrix and subtle cell
swelling
− Any organ or tissue can be involved, but edema is most commonly seen in
subcutaneous tissues, the lungs, and the brain
− Edema resulting from renal dysfunction often appears initially in parts of the body
containing loose connective tissue, such as the eyelids
Subcutaneous − Can be diffuse or more conspicuous in regions with high hydrostatic pressures
edema − Its distribution is often influenced by gravity
− It appears in the legs when standing and the sacrum when recumbent- termed
dependent edema
Pitting edema − Finger pressure over markedly edematous subcutaneous tissue displaces the
interstitial fluid and leaves a depression
Periorbital − A characteristic finding in severe renal disease
edema
Pulmonary − Lungs are often 2 or 3 times their normal weight, and sectioning yields frothy,
edema blood-tinge fluid- a mixture of air, edema, and extravasated red cells
Brain edema − Can be localized or generalized depending on the nature and extent of the
pathologic process or injury
− The swollen brain exhibits narrowed sulci and distended gyri, which are
compressed by the unyielding skull
Effusions − Hydrothorax- pleural cavity
− Hydropericardium- pericardial cavity
− Hydroperitoneum or ascites- peritoneal cavity
Transudative − Typically protein-poor, translucent and straw colored
effusion − An exception are peritoneal effusion caused by lymphatic obstruction (chylous
effusion), which may be milky due to the presence of lipids absorbed from the gut
Exudative − Protein rich, and often cloudy due to the presence of white cells
effusion
Congestion − Dusky, reddish-blue color (cyanosis) due to red cell stasis and the presence of
deoxygenated hemoglobin
Acute − Engorged alveolar capillaries, alveolar septal edema, and focal intraalveolar
pulmonary hemorrhage
congestion
Chronic − Caused by congestive heart failure
pulmonary − The septa are thickened and fibrotic, and the alveoli often contains numerous
congestion hemosiderin-laden macrophages called heart failure cells
Acute hepatic − The central vein and the sinusoids are distended
congestion − Because the centilobular area is at the distal end of the hepatic blood supply,
centri;obular hepatocytes may undergo ischemic necrosis while the periportal
hepatocytes- better oxygenated because of proximity to hepatic arterioles- may
only develop fatty change
Chronic − The centrilobular regions are grossly red brown and slightly depressed because of
passive cell death and are accentuated against the surrounding zones of uncongested tan
hepatic liver
congestion − Nutmeg liver
− There is centrilobular hemorrhage, hemosiderin-laden macrophages, and variable
degrees of hepatocyte dropout and necrosis
Thrombi − Can develop anywhere in the cardiovascular system and vary in size and shape
depending on the involved site and underlying cause
− Thrombi are focally attached to the underlying vascular surface, particularly at the
point of initiation. From here, arterial thrombi tend to grow retrograde, while venous
thrombi extend in the direction of blood flow; thus both propagate toward the heart
− The propagating portion of a thrombus is often poorly attached and therefore prone
to fragmentation and embolization
− Often have grossly and microscopically apparent lamination called lines of Zahn,
which are pale platelet and fibrin deposits alternating with darker red cell-rich layer
− Such laminations signify that a thrombus has formed in flowing blood
− Their presence can therefore distinguish antemortem clot from the bland
nonlaminated clots that occur postmortem
Arterial or − usually begin at sites of turbulence or endothelial injury
cardiac − frequently occlusive
thrombi − the most common sites in decreasing order of frequency are the coronary, cerebral,
and femoral arteries
− they typically consist of a friable meshwork of platelets, fibrin, red cells, and
degenerating leukocytes
− although these are usually superimposed on a ruptured atherosclerotic plaque,
other vascular injuries (vasculitis, trauma) may be the underlying cause
Venous − characteristically occur at sites of stasis
thrombi − aka phlebothrombosis
− almost invariably occlusive
− the thrombus forming a long luminal cast
− these thrombi form in the sluggish venous circulation, they tend to contain more
enmeshed RBC and few platelets, and are therefore known as red, or stasis
thrombi
− are firm, are focally attached to the vessel wall, and contain lines of Zahn
− the veins of the lower extremities are most commonly involved, however, upper
extremities, periprostatic plexus, or ovarian and periuterine veins can also develop
venous thrombi
− under special circumstances, they can also occur in the dural sinuses, portal vein,
or hepatic vein
Mural thrombi − thrombi occurring in heart chambers or in the aortic lumen
− abnormal myocardial contractions such as arrhythmias, dilated cardiomyopathy, or
myocardial infarction, or endomyocardial injury from myocarditis or catheter trauma
promotes cardiac mural thrombi,
− ulcerated atherosclerotic plaque and aneurysmal dilation are precursors of aortic
thrombi
Postmortem − can be mistaken for antemortem venous thrombi
clot − clots that form after death are gelatinous and have a dark red dependent portion
where red cells have settled by gravity and a yellow “chicken fat” upper portion, and
are usually not attached to underlying vessel wall
Vegetations − thrombi on heart valves
− bloodborne bacteria or fungi can adhere to previously damaged valves or can
directly cause valve damage; in either case, endothelial injury and disturbed blood
flow can induce the formation of large thrombotic masses (infective endocarditis)
− sterile vegetations can also develop on noninfected valves in persons with
hypercoagulable states, so called nonbacterial thrombotic endocarditis
− sterile verrucous endocarditis (Libman-Sacks endocarditis) can occur in the setting
 of SLE
Red infarcts − occur with venous occlusions (testicular torsion), in loose, spongy tissues (lung),
where blood can collect in the infarcted zone, in tissue with dual circulation (lung,
small intestine) that allow blood to flow from an unobstructed parallel supply into a
necrotic zone, in tissues previously congested by sluggish venous outflow, and
when flow is reestablished to site of previous arterial occlusion and necrosis
(following angioplasty of an arterial obstruction)
White infarct − occur with arterial occlusion in solid organs with end arterial circulation (heart,
spleen and kidney), and where tissue density limits the seepage of blood from
adjoining capillary beds into the necrotic area
Infarct − tend to be wedge shaped
− the occluded vessel at the apex and the periphery of the organ forming the base,
when the base is a serosal surface there may be an overlying fibrinous exudate
resulting from an acute inflammatory response to mediators release from injured
and necrotic cells
− fresh infarcts are poorly defined and slightly hemorrhagic