Tan, Mervyn C.

UST FMS Batch 2015 Section D

June 23, 2012

Dr. Alejandro Arevalo

Pathology SGD No. 1 Cell Adaptation, Cell Injury and Necrosis

CASE 1
The micrographs that follow show the gross and microscopic features
heart from a 40-year old male who has been hypertensive for the last 10 years.

of a

Gross
The left heart is from the patient and weighs 600 g.
The right heart is normal (for comparison). It weighs 350 g.
Gross, Transverse Section
This is the transverse section of the heart of the previous micrograph.
Observe the thickness of the venticles.
LV- left venticle, 4cm;
RV right venticle, 1.5 cm
MICROSCOPIC
This is the microscopic micrograph of the heart .
Take note of the fibers and the nuclei.
QUESTIONS
1. Identify the form of adaptation seen in this case.
The form of adaptation visible in this case would be hypertrophy.
This refers to an increase in the size of cells, resulting in an
increase in the size of the organ. We can readily see, in the gross
section of the heart, the prominent cardiomegaly.
We can also note that the heart is one of the organs which is
composed of muscle cells (myocardial fibers). Muscle cells
also known to be permanent cells (nondividing cells) and
these are also known to adapt by means of hypertrophy.
2. What is the stimulus?
The most probable stimulus for this case would be chronic
hemodynamic overload, which is the usual case for
cardiomegaly or hypertrophy of the heart. This may result
from either hypertension or faulty valves.
For muscles in general, the stimulus would be an increase
functional demand or increased workload.
Hypertrophy may also result from hormonal and growth
factor stimulation but not for this case.

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Explain the physiologic mechanism.

Hypertrophy is the result of increased production of cellular
proteins
Hypertrophy can be induced by the linked actions of
mechanical sensors (that are triggered by increased work
load), growth factors (including TGF-, insulin-like growth factor-1 [IGF-1], fibroblast growth factor), and
vasoactive agents (such as -adrenergic agonists, endothelin-1, and angiotensin II).
Mechanical sensors themselves induce production of growth factors and agonists which work coordinately to
increase the synthesis of muscle proteins that are responsible for the hypertrophy.
The two main biochemical pathways involved in muscle hypertrophy seem to be:
o The phosphoinositide 3-kinase/Akt pathway (postulated to be most important in physiologic, e.g.,
exercise-induced, hypertrophy)
o Signaling downstream of G protein-coupled receptors (induced by many growth factors and vasoactive
agents, and thought to be more important in pathologic hypertrophy)
Cardiac hypertrophy is associated with reinduction of ANF gene expression

Cardiac hypertrophy will eventually reach a limit beyond which enlargement of muscle mass is no longer

able to compensate for the increased burden. At this stage several regressive changes occur in the
myocardial fibers, of which the most important are lysis and loss of myofibrillar contractile elements.
In extreme cases myocyte death can occur by either apoptosis or necrosis.The net result of these
changes is cardiac failure, a sequence of events that illustrates how an adaptation to stress can progress
to functionally significant cell injury if the stress is not relieved

3. Describe the ultrastructural changes in the cardiac cells.

In the microscopic section of the cardiac muscle, we can note the enlargement of the muscle fibers and the
increase number of nucleus. Connective tissues are less apparent since the spaces are now being occupied
by hypertrophied muscle cell.
It may not be seen in this view but in another view, we could also see increments in the number of other
organelles.
4. What is the role of the cell cycle in this particular form of cellular adapation?
The cell cycle is important in the synthesis of more structural components of the cells. They synthesize more
proteins and the number of myofilaments also increases.
CASE 2
The following micrograph is from a 3- year old
boy with poliomyelitis
Section of the gastrocnemius muscle. The
arrows indicate some of the fibers with the adaptive
change
QUESTIONS
1. Identify the adaptive change seen in this
case.
The adaptive change observable in this
case would be atrophy.
Atrophy is reduced size of an organ or
tissue resulting from a decrease in cell
size and number.
2. What is the cause?
The most probable cause of atrophy in this case would be the loss of innervation or what we know as
denervation atrophy.
The normal metabolism and function of skeletal muscle are dependent on its nerve supply. Damage to the
nerves leads to atrophy of the muscle fibers supplied by those nerves.
3. Explain the pathophysiologic mechanism.
Atrophy results from decreased protein synthesis and increased protein degradation in cells. Protein
synthesis decreases because of reduced metabolic activity. The degradation of cellular proteins occurs mainly
by the ubiquitin-proteasome pathway.
o Nutrient deficiency and disuse may activate ubiquitin ligases, which attach the small peptide ubiquitin to
cellular proteins and target these proteins for degradation in proteasomes.
o This pathway is also thought to be responsible for the accelerated proteolysis seen in a variety of
catabolic conditions, including cancer cachexia
In many situations, atrophy is also accompanied by increased autophagy, with resulting increases in the
number of autophagic vacuoles.
o Autophagy (self eating) is the process in which the starved cell eats its own components in an attempt to
find nutrients and survive.
o Autophagic vacuoles are membrane-bound vacuoles that contain fragments of cell components. The
vacuoles ultimately fuse with lysosomes, and their contents are digested by lysosomal enzymes. Some of
the cell debris within the autophagic vacuoles may resist digestion and persist as membrane-bound
residual bodies that may remain as a sarcophagus in the cytoplasm.
4. What would be the ultrastructural features seen in the adaptive cells?
We would see decrease in cell size and organelles and these may reduce the metabolic needs of the cell
sufficiently to permit its survival.
Cells would contain fewer mitochondria and myofilaments and a reduced amount of rough ER.
5. Enumerate other possible causes that may lead to this type of cellular adaptation.
Decreased workload (atrophy of disuse)

When a fractured bone is immobilized in a plaster cast or when a patient is restricted to complete bedrest,
skeletal muscle atrophy rapidly ensues.
o The initial decrease in cell size is reversible once activity is resumed.
o With more prolonged disuse, skeletal muscle fibers decrease in number (due to apoptosis) as well as in
size; this atrophy can be accompanied by increased bone resorption, leading to osteoporosis of disuse
Loss of innervation (denervation atrophy)
o The normal metabolism and function of skeletal muscle are dependent on its nerve supply. Damage to the
nerves leads to atrophy of the muscle fibers supplied by those nerves
Diminished blood supply
o A decrease in blood supply (ischemia) to a tissue as a result of slowly developing arterial occlusive
disease results in atrophy of the tissue.
o In late adult life, the brain may undergo progressive atrophy, mainly because of reduced blood supply as
a result of atherosclerosis. This is called senile atrophy; it also affects the heart.
Inadequate nutrition
o Profound protein-calorie malnutrition (marasmus) is associated with the use of skeletal muscle as a
source of energy after other reserves such as adipose stores have been depleted. This results in marked
muscle wasting (cachexia). Cachexia is also seen in patients with chronic inflammatory diseases and
cancer. In the former, chronic overproduction of the inflammatory cytokine tumor necrosis factor (TNF) is
thought to be responsible for appetite suppression and lipid depletion, culminating in muscle atrophy.
Loss of endocrine stimulation
o Many hormone-responsive tissues, such as the breast and reproductive organs, are dependent on
endocrine stimulation for normal metabolism and function.
o The loss of estrogen stimulation after menopause results in physiologic atrophy of the endometrium,
vaginal epithelium, and breast.
Pressure
o Tissue compression for any length of time can cause atrophy.
o An enlarging benign tumor can cause atrophy in the surrounding uninvolved tissues. Atrophy in this
setting is probably the result of ischemic changes caused by compromise of the blood supply by the
pressure exerted by the expanding mass.
o CASE 3
o

o
The micrograph above is the
normal endometrium.

o
The micrograph above is a curettage from
a 50 year-old female who is complaining of irregular
vaginal bleeding

o QUESTIONS
1. Compare the glands and stroma of the 2 micrographs in terms of amount or density as well as the distribution of
the glands
The glands on the left have smaller and mostly circular or oval glands and there is much more stroma as
compared to the right.
The glands on the right are larger and have various sizes and irregular shapes. There seems to be a slight
gland-to-stroma-ratio.
2. Identify the form of cellular adaptation seen in the micrograph on the right.
We can observe hyperplasia on the 50 year old patients endometrium.
Endometrial hyperplasia is an important cause of bleeding and is defined as an increased proliferation of the
endometrial glands relative to the stroma, resulting in an increased gland-to-stroma ratio when compared with
normal proliferative endometrium.
3. What is the cause? Explain the pathologic mechanism.
Endometrial hyperplasia is associated with prolonged estrogen stimulation of the endometrium, which can be
due to anovulation, increased estrogen production from endogenous sources, or exogenous estrogen. Thus,
conditions associated with hyperplasia include obesity, menopause, polycystic ovarian disease (including
Stein-Leventhal syndrome), functioning granulosa cell tumors of the ovary, excessive cortical function (cortical
stromal hyperplasia), and prolonged administration of estrogenic substances (estrogen replacement therapy).
These are the same influences postulated to be of pathogenetic significance in some endometrial
carcinomas.
Mechanism:
o A common genetic alteration found in a significant number of hyperplasias and related endometrial
carcinomas is inactivation of the PTEN tumor suppressor gene. PTEN is located on chromosome 10q23.3
and encodes a dual-specificity phosphatase capable of dephosphorylating both lipid and protein
molecules. Its main function in tumorigenesis, as presently understood, is dephosphorylation of the lipid
molecule phosphatidylinositol (3,4,5)-trisphosphate (PIP 3), which blocks the phosphorylation of AKT, a
central factor in the phosphatidylinositol 3-kinase (PI3K) growth-regulatory pathway.
o When PTEN is inactive, AKT phosphorylation is enhanced, and it stimulates protein synthesis and cell
proliferation and inhibits apoptosis. Mutations in PTEN have been found in more than 20% of
hyperplasias, both with and without atypia, and in 30% to 80% of endometrial carcinomas, suggesting that
alterations in PTEN occur at a relatively early stage in endometrial tumorigenesis.
o It has been shown that loss of PTEN, resulting in the activation of AKT, can lead to phosphorylation of the
estrogen receptor in a ligand (estrogen)-independent manner. Thus, loss of PTEN function may activate
pathways normally activated by estrogen.
o
o CASE 4
o
This is a biopsy of the endocervix. Identify the 2 types of epithelium seen. What is the normal epithelium
of the endocervix?
Simple Columnar Epithelium
Stratified Squamous Non-Keratinizing Epithelium

o
o
o QUESTIONS
1. What is the form of cellular adaptation seen in this case?
What we can see is the presence of metaplasia. Metaplasia is a reversible change in which one differentiated
cell type (epithelial or mesenchymal) is replaced by another cell type.
It may represent an adaptive substitution of cells that are sensitive to stress by cell types better able to
withstand the adverse environment.
2. What is the usual stimulus that may lead to this type of cellular adaptation?
Irritation and trauma to the single layered cells, usually the epithelium or mesenchyme would cause this form
of cellular adaptation.
3. In the respiratory tract, give 2 possible stimuli that may lead to this form of adaptation.
Chronic Irritation
o Most common cause of respiratory metaplasia.
o In the habitual cigarette smoker, the normal ciliated columnar epithelial cells of the trachea and
bronchi are often replaced by stratified squamous epithelial cells.
Vitamin A Deficiency
o A deficiency of vitamin A (retinoic acid) induces squamous metaplasia in the respiratory epithelium.
o
o Light microscopic patterns of reversible cell injury

Left
o Observable cloudy swelling
o This is known as cellular swelling. Cellular swelling appears whenever cells are incapable of maintaining ionic
and fluid homeostasis and is the result of failure of energy-dependent ion pumps in the plasma membrane
o Cellular swelling is the first manifestation of almost all forms of injury to cells. It is a difficult morphologic
change to appreciate with the light microscope; it may be more apparent at the level of the whole organ.
o When it affects many cells, it causes some pallor, increased turgor, and increase in weight of the organ.
o On microscopic examination, small clear vacuoles may be seen within the cytoplasm; these represent
distended and pinched-off segments of the ER. This pattern of nonlethal injury is sometimes called hydropic
change or vacuolar degeneration. Swelling of cells is reversible. Cells may also show increased eosinophilic
staining, which becomes much more pronounced with progression to necrosis.
Right
o Fatty change occurs in hypoxic injury and various forms of toxic or metabolic injury. It is manifested by the
appearance of lipid vacuoles in the cytoplasm. It is seen mainly in cells involved in and dependent on fat
metabolism, such as hepatocytes and myocardial cells.
Ultrastructural changes of reversible cell injury include:
o Plasma membrane alterations, such as blebbing, blunting and loss of microvilli.
o Mitochondrial changes, including swelling and the appearance of small amorphous densities
o Dilation of the ER, with detachment of polysomes; intracytoplasmic myelin figures may be present
o Nuclear alterations, with disaggregation of granular and fibrillar element.
o
o Identify the type of necrosis seen in each micrograph. Give the possible causes and organs where they can occur.
Explain the etiopathogenesis of each:
o Necrosis:
The morphologic appearance of necrosis is the result of denaturation of intracellular proteins and enzymatic
digestion of the lethally injured cell (cells placed immediately in fixative are dead but not necrotic).
Necrotic cells are unable to maintain membrane integrity and their contents often leak out, a process that may
elicit inflammation in the surrounding tissue.
The enzymes that digest the necrotic cell are derived from the lysosomes of the dying cells themselves and
from the lysosomes of leukocytes that are called in as part of the inflammatory reaction.
Digestion of cellular contents and the host response may take hours to develop, and so there would be no
detectable changes in cells if, for example, a myocardial infarct caused sudden death.
The only circumstantial evidence might be occlusion of a coronary artery. The earliest histologic evidence of
myocardial necrosis does not become apparent until 4 to 12 hours later. However, because of the loss of

1.

2.

3.

4.

plasma membrane integrity, cardiac-specific enzymes and proteins are rapidly released from necrotic muscle
and can be detected in the blood as early as 2 hours after myocardial cell necrosis.
Coagulative Necrosis
Form of necrosis in which the
architecture of dead tissues is preserved for a span of at least some days.
The affected tissues exhibit a firm texture. Presumably, the injury denatures not only structural proteins but
also enzymes and so blocks the proteolysis of the dead cells; as a result, eosinophilic, anucleate cells may
persist for days or weeks.
Ultimately the 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.
Caseous Necrosis
Encountered most often in foci of
tuberculous infection.The term caseous
(cheeselike) is derived from the friable
white appearance of the area of necrosis.
On microscopic examination, the necrotic
area appears as a collection of
fragmented or lysed cells and amorphous
granular debris enclosed within a
distinctive inflammatory border; this
appearance is characteristic of a focus of
inflammation known as a granuloma.
Liquefactive Necrosis
Characterized by digestion of the dead cells,
resulting in transformation of the tissue into a
liquid viscous mass.
It is seen in focal bacterial or, occasionally,
fungal infections, because 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.
For unknown reasons, hypoxic death of cells
within the central nervous system often
manifests as liquefactive necrosis.
Enzymatic Fat Necrosis
Does not in reality denote a specific pattern of necrosis. Rather, it refers to focal areas of fat destruction,
typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the
peritoneal cavity.
This occurs in the calamitous abdominal emergency known as acute pancreatitis.
In this disorder 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, so derived,
combine with calcium to produce grossly
visible
chalky-white areas (fat saponification),
which
enable the surgeon and the pathologist to
identify
the lesions.
On histologic examination the necrosis
takes
the form of foci of shadowy outlines of
necrotic fat cells, with basophilic calcium
deposits, surrounded by an inflammatory
reaction.