Pathology Notes

Pathology Syllabus Notes
Pathology Syllabus Notes 1

I. General Pathology 1
II. Systemic Pathology 60
Cardiovascular pathology 60
Pulmonary pathology 82
Gastrointestinal pathology 95
Hepatic and Pancreatic Pathologies 108
Renal Pathology 116
Haematologic & Bone Marrow Diseases 121
Endocrinology Pathology 135
Pathologies of the Central Nervous System 146
Pathologies of infectious diseases 152
I. General Pathology
1. General and Special Pathology objectives. Basic terminology, purpose, tasks,
methods.
General and Special Pathology objectives
Pathology quite literally comes from ‘Pathos’ (suffering) ‘Logos’ (study), i.e. the study of
suffering.
Pathology can be seen as having two main objectives:

- Etiology - causes of disease (why a disease develops)
- Pathogenesis - development of disease in the body (how a disease develops)
General pathology is common changes in all tissues, for instance, all tissues can undergo
inflammation, cancer and aging, meanwhile, special pathology looks to examine the etiology
and pathogenesis of particular specialized organs, e.g. pneumonia, breast cancer.
It can therefore be said that pathology provides the scientific foundation for the practice of
medicine.
Basic terminology, purpose, tasks, methods

Here we will consider some core terms and their meaning in the context of Pathology:
- Disease
- ‘Expression of discomfort due to structural or functional abnormality’
- Disease can be:
- Inflammatory
Pathology Notes - Feb 2019
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- Acute/Chronic
- Congenital/Acquired
- Genetic/environmental
- Mild/Moderate/Severe
- Has four aspects
- Etiology (causal agent)
- Pathogenesis (mechanism of change)
- Morphology (structural change)
- Clinical expression
- Death
- Clinical Death (reversible cessation of blood circulation and breathing)
- Biological Death (irreversible)
The primary methods of Pathology are:

- Autopsy
- Clarifies cause of death and helps improve future treatment
- Two types
- Hospital - for patients that died of natural causes
- Or Forensic - legal case concerned
- Includes External examination, Dissection and Pathology protocol
- Biopsy (known as Necroscopy in dead tissue)
- Histological
- Investigation of tissue, methods include
- Surgery
- Endoscopy
- Large needle biopsy
- Cytological
- Investigation of isolated cells
- May be body fluids, fine needle biopsy of vaginal smears
Other methods in Pathology include
- Electron microscopy
- Immunofluorescence
- Immunohistochemistry
- Molecular pathological methods (e.g. PCR) and others.
2. Cellular injury; common causes and mechanisms
Cells exist in homeostasis. Where they are subject to stress

they attempt to adapt. Where they are unable to adapt they
become ‘Injured cells’. Common methods of adaptation
include hypertrophy (increase in cellular size), Hyperplasia
(increase in cellular number), atrophy (shrinkage of cell by
loss of substance) and metaplasia (replacing of cells by
different cellular types, think tough calluses of skin).
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The most common cause of cellular injury is Hypoxia, or oxygen deficiency, as it prevents
aerobic oxidative respiration, and the conversion of carbohydrates into ATP. Hypoxia can
often be caused by Ischemia, lack of blood supply to an affected area, but also as a result of
pneumonia (lack of oxygen in blood), anemia (reduction of oxygen
carrying capacity of blood) and CO poisoning.
Other important causes include:

- Chemical agents
- Such as high glucose, salt, oxygen, CO or other
toxic agents
- Infectious agents
- Immunologic reactions
- Physical agents
- Nutritional imbalances
- Genetic defects
- Aging
These problems cause the cell to become nonfunctional, this

dysfunction leads to cellular injury, we’ll now consider the
mechanism of cell injury. The following mechanisms of cell injury are the most common,
and usually combined:
- Depletion of ATP (failure of energy --- Necrosis)
- Causes; Influx of Sodium and Calcium ions and osmotic swelling due to
failure of ATP dependent ion pumps
- ATP depleted cells being anaerobic metabolism to derive energy from
glycogen (Glycolysis)
- Results in decrease of pH, creating acidic environment and damaging
enzymes.
- Causes clumping of nuclear chromatin, pyknosis, leading to cellular
necrosis.
- Damage to Mitochondria (leads to ATP depletion, high Ca2+ and ROS common
causes)
- Influx of calcium (activates enzymes with damaging cellular effects)
- Accumulation of Oxygen-Derived free radicals (Damages membrane and DNA)
- Defects in membrane permeability
- Damage to DNA and proteins
- Disruption to cell membrane
3. Reversible cell injury due to compromised ionic transfer (cellular swelling):

granular degeneration, vacuolar degeneration, hydropic change
Cellular injury can be reversible or irreversible. Multiple morphological changes can be
shown in reversible damage:
- Cellular swelling (result of defective energy-dependent ion pumps leading to poor
fluid homeostasis).
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- Fatty change (increase in number of large lipid vacuoles in cytoplasm due to

organelle failure)
- Plasma membrane damage (e.g. blebbing)
- Dilation of ER
- Nuclear alterations
One of the common causes of cell injury, and the precursor to many conditions, is the
accumulation of abnormal amounts of substances, this can be caused by hypoxia, which
causes damage to the sodium potassium membrane pump. The Sodium-potassium pump
is of course an active one, thereby, what we are seeing is Hypoxia leading to disruption of
the Krebs/ETC mechanism, leading to reduction in available ATP, leading to
Sodium-Potassium pump disruption.
Reduction in ATP results, in fact, in four significant cellular changes:

1. ATP-dependent sodium pump is reduced (what this question is specifically tackling)
2. Increase in anaerobic glycolysis (as will be considered in question 6)
3. Failure of ATP-dependent Ca2+ pumps leading int increase in intracellular Calcium
4. PRolonged depletion of ATP leads to structural disruption of ER and RER.
The failure of the Na/K pump leads to leakage of potassium into the ECM, with sodium
welling and increased intracellular
and water moving into the cell, causing cellular s
pressure, possibly leading to membrane damage.
Macroscopically we see a change in colour to pallor, increased turgor (hydrostatic

pressure), and increased weight. Microscopically we see small clear vacuoles within the
cytoplasm, representing pinched-off segments of endoplasmic reticulum.
From what I can tell, the terms ‘granular degeneration, hydropic change and vacuolar
degeneration’ are all synonyms for this pattern of pathological damage.
4. Lipid accumulation in parenchymal and stromal cells. Lipid phagocytosis.
A reminder:
- Parenchymal cells = functional parts of an organ in the body
- Stroma = structural tissue of organs (i.e. CT)
(so basically, this question is lipid accumulation in ALL of the cells in the body! :D )
There are four pathways for abnormal intracellular accumulations:

1. Inadequate removal of a normal substance due to packaging or transport defects
2. Defects in folding, packaging, transport or secretion of abnormal endogenous
substance
3. Failure to degrade due to inherited enzymopathy
4. Deposition and accumulation of abnormal exogenous substance as we don’t have
the correct machinery to degrade, transport or store
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Lipid accumulation, also known as Steatosis, is the abnormal retention of lipids in a cell. It is
the product of the first of the above four methods, inadequate removal of a normal
substance. Steatosis is commonly seen i the liver, the major organ involved in fat
metabolism, but can also be seen in the heart, skeletal muscle, kidney and other organs.
Excess lipid accumulates in vesicles that displace in the cytoplasm, it can be divided into two
categories:
- Macrovesicular steatosis - where the fat vacuoles displace the nucleus
- Microvesicular steatosis - where the fat vacuoles do not displace the nucleus
Lipid accumulation is most common in

the liver and can be the product of:
- Excessive entry of lipids
- Enhanced FA synthesis by
hepatocytes
- Increased esterification of FA
into TAGs
- Decreased apoprotein
synthesis (remember
apoproteins are what Lipids
leave the liver as)
- Decreased oxidation of FA by
mitochondria
- Impaired lipoprotein excretion
Other lipid accumulations include:

- Cholesterol and cholesteryl ester accumulation
- In atherosclerosis
- In hereditary hyperlipidemia (formation of xanthomas, fat tumours)
Lipid phagocytosis occurs in hypertension when lipids are forced into intimal wall of the
vessels causing foam cells.
5. Complex lipid accumulations: lipidosis
Lipidosis is a group of inherited metabolic disorders where harmful amounts of fats or

lipids accumulate in the body’s cells. These are enzymopathies, where there is a failure to
breakdown lipids. Tissue damage is classically seen in the brain, peripheral nervous system,
liver, spleen and bone marrow.
There are two main classifications of lipidosis:

- Sphingolipidoses
- Related to sphingolipid metabolism
- Include Niemann-Pick disease, Fabry disease, Krabbe disease, Farber
disease and others
- Other
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- Non-sphingolipid related disorders

- Include fucosidosis, Schindler disease and Wolman disease
These can be autosomal recessive or X linked.
Lipidosis is considered part of a wider group of disorders known as lysosomal lipid storage
diseases. Lysosomes, you’ll remember, are sacs of enzymes which digest large molecules
and pass on the fragments for use, they are, in effect, the catabolic agent of lipids.
Diagnosis of lipidosis is done through clinical examination, biopsy, genetic testing,

molecular analysis of cells or tissues and enzyme assays. There is no specific
treatment, however we have a number of therapies for certain conditions to alleviate
symptoms.
6. Abnormal intracellular glycogen accumulations. Glycogenoses
One of the common forms of reversible cellular injury is the abnormal accumulation of cells,
common intracellular accumulations can be:
- Glycogen
- Proteins
- And Pigments (both exogenous and endogenous)
Excessive intracellular deposits of glycogen are associated with metabolism abnormalities

of glucose or glycogen. Such glucose or glycogen deposits appear as water-clear
vacuoles and are PAS positive staining. Accumulation occurs due high glucose
concentrations. Such accumulations are common in:
- Poorly controlled diabetes mellitus
- Found in renal proximal tubules, the liver and cardiac myocytes
- Glycogen storage diseases (aka Glycogenoses)
Glycogenoses (Glycogen storage diseases) are an inherited genetic disorder that results in
enzymatic defect in synthesis and/or breakdown of glycogen (remember, glycogen is the
bodies store for glucose). These conditions are Autosomal recessive, and result in
excessive accumulation of glycogen in the tissues.
There are various forms of glycogenosis, based on the specific enzyme deficiency, based
on pathophysiology, we can break Glycogenoses into three categories:
1. Hepatic type
a. Deficiency of the hepatic enzyme involved in glycogen metabolism
b. Leads to enlargement of liver due to high glycogen and hypoglycemia due to
lack of free glucose
c. Von Gierke’s disease is an example
2. Myopathic type
a. Deficiency of the skeletal muscle enzymes involved in glycolysis are deficient
b. Leads to muscle weakness
c. E.g. McArdle’s disease
3. Generalised glycogenosis
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a. Any other enzymopathy related to glucose metabolism

b. Example is Pompe disease
7. Hemoglobin-derived pigment accumulations. Hemosiderosis. Types of

jaundice.
So, pigments can be Exogenous (from outside the body, such as Carbon) or Endogenous
(from within the body. Endogenous pigments can then be broken down into:
- Hemoglobin derived organic pigments (Hemosiderin, bilirubin)
- Non Hemoglobin derived pigments (Melanin, Lipofuscin)
Hemoglobin consists of Gobin (with 2 alpha and 2 beta chains) and Heme, a protoporphyrin
with an iron chelate. This in turn can be broken down into two pigments, Hemosiderin and
Bilirubin.
Hemosiderin is only found within cells and is a complex of ferritin (stored iron) and other
material. Where the body has excess iron it can lead to an alteration of cellular colour
visualized by light microscopy. The dominating colour is golden yellow to brown. Build up
of hemosiderin can be a product of local or systemic excess iron.
Systemic build up can be a product of:

- Increased iron absorption
- Impaired iron utilization
- Hemolytic anemias (early degradation of RBCs)
- Transfusions
The most obvious build up of systemic hemosiderin is in the mononuclear phagocytes of
the liver, bone marrow, spleen and lymph nodes.
Meanwhile, excess local iron can be as a result of a hemorrhage, such as a bruise,

where the sudden lysis of a large number of RBCs creates a large amount of iron, which is
consequently stored as hemosiderin.
Finally in relation to Hemosiderin, there are a number of genetic disorders which cause the
body to accumulate excess iron, with mutations to the HFE gene on chromosome 6 leading
to poorly regulated iron levels and deposition of hemosiderin throughout the body.
Secondly, Bilirubin is the end product of heme degradation. Normal bilirubin production is
approximately 0.2-0.3 gm/day and is derived from the breakdown of erythrocytes. The
process of production is as follows:
- Heme is degraded into Biliverdin, which is reduced into Bilirubin which in turn binds
to albumin to travel through the blood to the liver
- The Bilirubin-Albumin complex arrives to the liver where the bilirubin is then
secreted into bile
- Gut bacteria then conjugate the bilirubin in the bile and degrade it into
urobilinogens
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- Approximately 20% of urobilinogens are the reabsorbed into the ileum and
colon
Jaundice and Cholestasis are two conditions related to retention of bilirubin, Jaundice is
solely bilirubin retention, while Cholestasis is the retention of bilirubin and other
solutes in bile (e.g. bile salts and cholesterol). Both conditions cause a yellowing o
f the
skin, eyes and mucus membranes, with pale-stools.
There are three main types of Jaundice:

- Hemolytic - increased destruction of erythrocytes
- Increased unconjugated bilirubin and increased feces pigment
- In effect, we’re seeing here more bilirubin than the body can deal with
- Obstructive - Cholestasis is a type of obstructive jaundice, sees blockage of bile duct
- INcreased conjugated bilirubin, decreased bilirubin in stool
- In effect, the bile is unable to successfully leave the body
- Hepatocellular - damage to hepatocytes that are responsible for dealing with bilirubin
- Increased conjugated and unconjugated bilirubin
Jaundice may also be the product of inherited genetic diseases, such as:
- Gilbert syndrome
- Dubin-Johnson syndrome
- Rotor syndrome
8. Non-hemoglobin derived pigment accumulations: melanin, lipofuscin

There are only two non-hemoglobin, endogenous pigment accumulations that we care
about, and apparently there isn't much to say. But let’s start at the top.
Melanin is an endogenous brown-black pigment produced by melanocytes located in the

dermis, acting as a screen to harmful UV radiation. A number of conditions are the
product of increased melanin levels:
- Pigmented nevus
- Fancy name for moles, grow on the skin
- Clusters of melanocytes, can darken after sun exposure
- Addison’s disease
- Aka primary adrenal insufficiency
- Endocrine disorder where the adrenal glands don’t produce enough steroid
hormone
- Hyperpigmentation of the skin may be visible, especially in areas not usually
exposed to sun (e.g. nipple, buccal mucosa, crease of hand)
- Melanoma
- Cancer that derives from melanocytes
- May develop from pigmented nevus (mole)
- Caused by UV light exposure
On the reverse, some conditions are the product of decreased melanin:

- Albinism
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- No tirosinase enzyme therefore no production of melanin in melanocytes

- Vitilogo
- Local deficiency of melanin in the dermis
Meanwhile Lipofuscin is an insoluble brownish-yellow granular material that

accumulates in the heart, liver and brain as well as other tissues. It is composed of lipid and
protein complexes that derive from free-radical catalyzed peroxidation of
polyunsaturated lipids of subcellular membranes.
This is basically a wear and tear pigment that appears after a cell has been exposed to
oxidative stress and the lipids have been oxidised and mashed with some proteins!
9. Exogenous pigments - types, organ sites

Common examples of exogenous pigments are:
- Accumulation of Carbon (black), known as Anthracosis
- Commonly occurred from air pollution
- Inhaled and phagocytosed by alveolar macrophages, where it is then
transported through lymph to regional tracheobronchial lymph nodes where it
aggregates
- Heavy accumulation can induce emphysema or fibroblastic reaction
- Tattooing
- Pigment artificially injected into the dermal part of the skin.
- The ink particles used are too large to be consumed by macrophages so
remain in the dermal region.
Really not sure what else to add here, only one slide in the lecture on this, nothing in
Robbins, shout if you have something else!?
10. Extracellular accumulations: hyalinosis, fibrinoid swelling

A reminder, that extracellular tissue consists of:
- Fibrous structural proteins (elastin and collagens)
- Water hydrated gels (proteoglycans and hyaluronan)
- Adhesive glycoproteins
Pathologies lead to a change in quantity and/or quality of these normal components.
We classify accumulations in the ECM as follows:

- Disorders in the metabolism and structure of collagen
- Disorders in the metabolism and structure of elastin
- Disorders in the content of the proteoglycans
- Abnormal accumulations in the ECM
- Including proteins
- Fibrinoid
- Hyalin
- Amyloid
- Inorgnics
- Ca2+
- Urates (e.g. Uric acid)
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Hyalinosis
Hyaline is a morphological description of a non-structured ‘glassy’ structure, made of a
heterogenous mix of proteins, lipids and carbohydrates. Hyalinisation can occur in the
ECM of any tissue, below we explore some examples:
- Vascular hyaline
- Due to nonenzymatic glycosylation of proteins in the basement membrane of
vessels
- Is associated with hypertension, usually a secondary product, as high
pressure forces proteins into the ECM
- Can lead to Glomerulonephritis
- Glomerulonephritis
- High pressure in the afferent arteries of the kidneys leads to build up of
Hyaline around the glomeruli. (NOTE SLIDE - HYALINOSIS RENIS)
We can also divide hyalinosis according to the mechanism of formation:
- Hyaline as a product of of fibrinoid changes
- A product of damaged perivascular stroma
- Hyaline in the finale of plasmatic impregnation
- A product of buildup in the vascular wall
- Local hyalinosis as product of inflammation
- Hyalinosis as a product of necrosis
- Hyalinosis as a product of sclerosis (hardening of tissue)
Fibrinoid swelling
Fibrinoid swelling, quite simply means swellings that have the characteristics of fibrin. It
is the morphological description of non-structured heterogeneous substance
predominantly made of plasma proteins. It is stained by Van Gieson (yellow).
There are three main forms of Fibrinoid swelling

- Fibrinoid in precipitation of immune complexes
- A product of systemic connective tissue diseases
- Fibrinoid in accumulation of plasma proteins
- Product of hypertension
- Fibrinoid in mucosal necrosis
- Such as in a chronic peptic ulcer
The first type is linked with systemic connective tissue diseases, such as rheumatoid
arthritis. Antibodies join with plasma proteins to form fibrin-like masses which can be
seen in areas such as the skin, organs and vessels.
Secondly, fibroids forming as a product of plasma protein accumulation, in malignant

hypertension the smooth muscle cells undergo hyperplasia and there is basement
membrane duplication, leads to collection of plasma proteins in a fibrin mass.
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In the final type, fibrinoid in mucosal necrosis, we see firbinoid swelling occurring in
areas of chronic inflammation and damage, such fibrinosis often accompanies tissue
granulation and fibrinoid necrosis.
11. Extracellular accumulations: amyloidosis. Types of amyloidosis, pathogenesis,

microscopic & gross organ pathomorphology. Histochemical staining methods
This is, in effect, the continuation of the above, except amyloidosis is a more common and
significant accumulation, indeed it gets its own powerpoint!!!
Amyloid is an abnormal protein substance which can be deposited among the cells in
various tissues in a condition known as amyloidosis.
Amyloidosis is a product of protein misfolding, leading to mutant proteins (like in X-men,

just less sex). It is heterogenous, although always visually the same, with nonbranching
fibrils in a beta-sheet formation.
There are four main types of amyloidosis, based on the particular protein that has been
misfolded (although there are actually 30 types in total)
- AL- amyloid (Amyloid light chain)
- Derived from light chains
- AA-amyloid (Amyloid-associated)
- Derived from serum associated amyloid (SAA), an acute phase reactant
- Beta Amyloid
- Derived from amyloid precursor protein
- Endocrine amyloid
We are also able to divide amyloidosis based on the pathology itself, we split this based on
location of amyloids:
- Generalized systemic amyloidosis
- Amyloids deposited throughout the body
- Primary (AL amyloid), secondary (reactive, result of inflammation), or
hereditary (both AA amyloid)
- Localized
- Amyloids found in a single ogan
Pathogenesis: Amyloidosis is the product of the following chain

- Excessive production of proteins that are prone to misfolding
- Mutations that produce proteins that cannot fold properly clump together
- Defective or incomplete degradation of these proteins
- They then need to be stored, so we stick ‘em wherever they’ll
go
Morphology
Kidney (NOTE SLIDE):
- Gross appearance may be unchanged or large, pale, gray and firm
- Microscopically, deposits are found in glomeruli, the interstitial peritubular tissue and
in the walls of blood vessels
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Spleen (NOTE SLIDE):

- Gross appearance shows enlargement, firm in consistency with pale gray, waxy
deposits inside
- Microscopically, 2 patterns, in the folliculi we see tapioca like granules while in the
sinuses and pulp there are large sheetlike deposits of amyloids
Liver
- Gross appearance shows massive enlargement, very pale, grayish and waxy
- Microscopically, deposits found in the space of Disse
Heart
- Gross appearance may be unchanged, or may be minimal enlargement with gry-pink
subendocardial elevations
- Microscopically, deposits found throughout the myocardium between myocardial
fibers
Other organs that may be affected include adrenals, thyroid, pituitary and GI tract.
Staining
- Meti Violet and cresyl violet- show as red
- Congo red - shows as red under light microscope and green under polarized light
- Thioflavin S - yellow green fluorescence
12. Extracellular accumulations of calcium and uric acid salts

Deposition of calcium in ECM
The deposition of calcium in the ECM can be a product of local causes, such as necrosis,
as is the case in atherosclerosis leading to calcification of heart valves, or systemic causes,
such as in hypercalcemia, leading to problems such as renal failure, destruction of bone
and hyperparathyroidism.
Macroscopically calcium deposits are visible as fine white granules while

microscopically we see extracellular basophilic deposits.
Deposition of urates in ECM

Deposition of urates in the ECM is commonly associated with conditions such as Gout and
Lesch-Nyhan syndrome.
Excess uric acid builds up and is deposited in the joints, the build up can be a product of
an enzymopathy, excess consumption of animal meat, or super-activity of the
enzymes responsible for purine production (phosphoribosyl pyrophosphate
synthetase, PRPP), in effect, we either have too much uric acid, or are unable to remove it,
so we dump it in the joints.
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13. Metabolic and structural abnormalities of collagen, elastin and proteoglycans.

Mucopolysaccharidoses
Collagen
Collagen is the main fibrous component of skin, bone, tendons and cartilage, in total it is a
third of our total protein.
Collagen is made of 3 polypeptide alpha chains coiled in a left handed triple helix.
There are 3 amino acids per turn, and Glycine occupies every third position in the repeating
sequence. Additionally, collagen has a high content of proline and hydroxyproline and is
further stabilised by inter-chain hydrogen bonds.
There are 28 types of collagen, but there are five main ones we should concern ourselves
with:
- Collagen I - skin, tendon, vascular ligature, organs, bone
- Collagen II - cartilage
- Collagen III - reticulate
- Collagen IV - forms basal lamina
- Collagen V - cell surface, hair and placenta
Collagen disorders are generally the product of genetic defects or nutritional

deficiencies that affect biosynthesis, there are in effect three categories of disorder:
- Increased collagen synthesis (fibrosis)
- Abnormal structure of collagen
- Abnormal collagenolysis
Increased collagen synthesis

- Fibrosis is the product of increased activity of lysyl-oxidase, a fibroblast that lays
down connective tissue (collagen and glycosaminoglycans)
- The process is initiated when immune cells such as macrophages stimulate
fibroblasts
- The most well known one is TGF beta, so released by macrophages
- Fibrosis is generally the product of inflammation or damage, examples include:
- Pulmonary fibrosis (e.g. Cystic fibrosis)
- Liver Cirrhosis
- Atrial/Endomyocardial fibrosis
- Glial scarring (in the brain)
- Macroscopically there is a decrease in organ size and an increase in density
- Microscopically there is an increase in collagen in the ECM, visible with Van Gieson
staining (collagen stains red)
Abnormal structure
This is generally the product of genetic defects which result in abnormal structure, there are
two main conditions to consider:
- Marfan’s syndrome
- AD disorder, affecting fibrillin 1, a major component of microfibrils found in
ECM, including elastins
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- Product of FBN1 gene mutation

- Morphologically shows Arachnodactyly (spider fingers), hyperextensibility of
joints, spinal deformities, bilateral dislocation/subluxation of eyes and mitral
valve regurgitation with congestive heart failure
- Ehlers-Danlos syndrome
- Defects in synthesis of assembly of collagen, comes in 6 variations
- Produces 30 distinct types of collagen
- Pathophysiology
- Deficiency in lysyl hydroxylase enzyme
- Deficient synthesis of type III collagen, result of COL3A1 gene
mutation
- Morphology shows fragile, hyperextensible skin, poor wound healing,
hypermobility of joints and rupture of internal organs
Abnormal collagenolysis
- Increased activity of collagenolytic enzymes
- Decreased activity of atnicollageneases
- e.g. α1-antitrypsin
- AR disorder of AAT gene, chromosome 14, decreased antitrypsin production
from hepatocytes
Elastin
Elastin is an elastic protein found in the CT which gives it its elasticity. It is composed of
Elastic fiber and fibrillar fibrillin proteins, coded for the by the ELN gene on
Chromosome 7.
There are two main types of disorders associated with elastins:

- Decreased elastogenesis
- Product of aging
- Ectasia of the aorta
- Senile emphysema
- Increased/abnormal elastogenesis (elastosis)
- Senile elastosis of skin
- Endocardial fibroelastosis
- Of newborn (Left heart ventricles) or aged (right heart ventricles)
Proteoglycans
These are heavily glycosylated proteins (that is to say, they have had many
carbohydrate, read glucose, molecules added). Proteoglycans can be characterised as
large and small beased on size, and help to fill in the ECM. They are especially noticable
in cartilage where they bind to collagen to help give collagen its structure.
They are synthesised by ribosomes and pass by the rER to be glycosylated before
passing into the ECM.
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Mucopolysaccharidoses
The inability to break down proteoglycans comes under a group of disorders known as
mucopolysaccharidoses. The body l acks specific lysosomal enzymes that then leads to
the accumulation of proteoglycans within the cell.
This group consist of about 40 genetic defects, all of which show a number of different
symptoms, including:
- Damage to neurons
- Impaired motor function
- Possible intellectual impairment
- Hearing loss
- Communicating hydrocephalus (abnormal reabsorption of CSF)
- Rough facial symptoms
- Dawfism
- Dysplasia of bone
- Hepato and splenomegaly
Prevalence is about 1 in 25,000 live births in the US, and all conditions are AR (*with the
exception of MPS II which is X-linked recessive)
There are seven clinical types, and numerous subtypes, we’ll take a look at these in brief
here:
- MPS IH - Hurler syndrome
- MPS IH/S - Hurler-Scheie syndrome
- MPS IS - Scheie syndrome
- MPS II - Hunter syndrome*
- MPS III - Sanfilippo syndrome (A-D)
- MPS IVA - Morquio syndrome (A+B)
- And others that i’m not going to list because...well...no
14. Irreversible cell injury - cell death. Types of necrosis; microscopic & gross
pathomorphology. Apoptosis.
As cells undergo extensive stress they will try to adapt, where that adaptation becomes
irreversible adaptation the cell is forced down the path of cell death. As we know, cell death
can be Necrosis (unplanned) or Apoptosis (planned). Some causes of cell injury include:
- Hypoxia and Ischaemia
- Physical agents
- Chemical agents
- Microbiology
- Immunological agents
- Nutritional factors
- Aging
- And others
These factors result in some common pathogenetic pathways that damage the cell:
- Many of these etiological factors ultimately lead to failure of ATP generation and ATP
depletion
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- This reduces activity of ATP dependent Na+/K+ pumps

- Results in sodium (and therefore water) accumulation in cell
- Therefore causes cellular swelling
- Failure of calcium pump leading to membrane damage
- Compensatory increase in anaerobic glycolysis leads to build up of lactic
- decreased intracellular pH as a result
- Decreased enzyme activity
- Prolonged ATP depletion results in detachment of ribosomes from rER
- Hypoxia also seems to increased ROS concentration, causing lipid peroxidation on
cell membrane, cross linking of proteins and DNA damage
Where the damage to the cell is persistent or excessive, injured cells pass the point of no
return and their damage becomes irreversible, there are three key indicators for this point:
- Inability to restore mitochondrial function
- Structure and function of plasma membranes and intracellular membranes
- The loss of DNA and chromatin structural integrity
Necrosis - Types of Necrosis

Necrosis is the local death of cells, tissues, part or sometimes an entire organ, there are two
essential changes that characterise all types of necrosis:
- Cell digestion by lytic enzymes
- Denaturation of proteins
The key cytoplasmic changes are:
- A homogeneous cytoplasm
- Which appears highly eosinophilic due to increased binding of eosin to denatured
proteins
Nuclear changes to the cell can be seen as:
- Karyopyknosis (Nuclear shrinking)
- Karyorrhexis (Nuclear fragmentation)
- Karyolysis (Nuclear fading)
There are five types of Necrosis, these are:

- Coagulative necrosis (e.g. Necrosis Renis and Necrosis Myocardium) (NOTE
SLIDES FOR BOTH)
- Liquefactive necrosis (e.g. Necrosis cerebri) (NOTE SLIDE)
- Caseous necrosis (e.g.. Necrosis Lymphonodi) (NOTE SLIDE)
- Fat necrosis
- Fibrinoid necrosis
Coagulative necrosis
This is the most common form of necrosis and is the result of hypoxic death of cells in all
tissues except for the brain. It is the result of denaturation of proteins and blocked
proteolysis.
The gross morphology shows a sharply demarcated line, with a grayish-white zone
surrounded by a hemorrhagic zone.
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Histologically speaking there is no evidence of necrosis until 8-12 hours after damage,
there is preservation of the basic outline of the cell for at least a day and shadows of the
pre-existing organelles can be seen.
Denaturation of the proteins affects the macrophages responsible for cellular clearance,
leading to an inflammatory response.
Liquefaction necrosis
Liquefaction necrosis sees the softening and liquidation of tissue, this is a result of either
lysosomal enzymes being released by the necrotic cell, or the action of neutrophils
within the tissue. The most common examples of this form of necrosis are within the
brain and abscess cavities due to their low protein levels.
Gross morphology shows a soft centre with necrotic debris, and the formation of a cyst wall.
Histologically the cyst space contains necrotic cell debris with macrophages and phagocytic
material.
Caseous necrosis
‘Cheese’ necrosis is most commonly found in TB infections. Is almost a mix of coagulative
and liquefactive necrosis, cells do not maintain their outline (as in coagulative), nor do
they liquefy (as in liquefaction).
Morphologically we see this pale white, crumbling, almost cheese like, structure, while
histologically we see a fully homogenised central zone with giant langhans type cells.
Fat Necrosis
This is a special form of death occurring in acute pancreatic necrosis and traumatic fat
necrosis (often in the breast).
In pancreatic necrosis, the process sees the release of pancreatic lipases from injured
tissues, causing necrosis of the pancreas and other fat droplets in the peritoneal cavity.
The fat is broken down into Free Fatty Acids, which combine with calcium to form calcium
soaps in a process known as saponification.
Morphologically we see yellowish white, firm deposits through the peritoneal cavity, with a
histological picture showing cloudy, cell free tissue.
Fibrinoid necrosis
This form of necrosis is associated with the accumulation of fibrinoid. Fibrin is in effect a
heterogeneous protein structure which gets laid down in extreme immune reactions
involving blood vessels, in what is known as Type III hypersensitivity reactions.
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The process in effect sees Antigens and Antibodies are deposited in the walls of
arteries forming immune complexes, these immune complexes come together with
fibrin which forms this ‘fibrinoid’ structure.
Histologically Fibrinoid necrosis is seen as a bright pink amorphous structure when

stained with H&E staining. The necrotic focus is surrounded by nuclear debris of
neutrophils.
Apoptosis
Apoptosis on the other hand is the programmed death of cells. Importantly, inflammation
does not occur.
Apoptosis can be initiated either through the intrinsic pathway, as it senses cell stress, for
instance a virus, or extrinsic pathway, as it has received a signal from other cells. Both
pathways activate caspases, which are enzymes that degrade proteins.
The extrinsic pathway sees activation via a T-cell targeting a cell and producing a
signaling protein called Fas ligand. The Fas ligand binds to its receptor, Fas, on target cells,
which in turn binds to proteins that link the receptor to procaspase-8 molecules. These
aggregate and cleave one another, initiating a proteolytic cascade, leading to
apoptosis.
The intrinsic pathway depends on mitochondrial. When cells are stressed, damaged or
abnormal, pro-apoptotic signals are released which induce mitochondria to release
cytochrome c into the cytosol, where it binds and activates protein Apaf-1. This causes
Apaf-1 to aggregate into an apoptosome, which recruits procaspase-9 molecules, which
activate and trigger a caspase cascade, leading to apoptosis.
As the caspases start to break down the cell, it shrinks and sends out distress signals
which attract macrophages to degrade the shrunken cells leaving no trace and preventing
any inflammatory response. We can view Apoptosis in the following stages:
● Loss of mitochondrial function and caspase activation
● Fragmentation of DNA by Endonucleases
● Shrinkage of nuclear and cell volumes due to destruction of cytoskeleton
● Cell membrane undergoes blebbing where proteins are degraded
● Formation and phagocyte removal
Apoptosis is an integral part of a healthy organism. In neonates, during development, tissue

present between the digits is removed by apoptosis. Furthermore, to prevent cancers and
malformations, damaged cells must be successfully removed. However, AIDS and
Alzheimer’s are examples of conditions that disrupt the Apoptosis process and cause
increased apoptosis, leading to pathology.
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15. Ischemic necrosis - infarction. Morphogenesis. Types of infarctions - anemic,

hemorrhagic. Organ sites. Microscopic & gross pathomorphology
Ischemia is diminished blood flow to the tissue, compromising delivery of substrates for
glycolysis. This causes no/very little ATP to be formed, meaning the active transport of the
sodium/potassium pumps fails, causing cellular s welling and eventually necrosis along
with increase in ROS and resultant damage. Most of this has been covered above really,
just re-read.
An infarction is obstruction of the blood supply to an organ or tissue (generally by

thrombus) causing local tissue death. It is the single word for ischemic necrosis. We can
classify infarctions based on their histopathology:
- White infarction - anemic infarcts
- Effects solid organs (e.g. spleen, heart and kidneys
- Solidity limits nutrients that can flow to the area, it is in affect an absolute
necrotic process
- Red infarctions - hemorrhagic infarcts
- Generally affect lungs and other loose organs (testis, ovaries, SI)
- Occlusion occurs in loose tissue where some nutrients is able to get
through, or in areas with dual circulation (e.g. lung and small intestine)
We can also divide infarcts based on organ site:

- Heart = Myocardial infarction
- Brain = ischemic stroke
- Lung = pulmonary infarction
- Spleen = splenic infarction
- Limb = limb infarction
Gross presentation is red or white depending on type of infarct, while histological findings
show that of ischemic necrosis (cellular swelling and blebbing etc), in the CNS we see
liquefactive necrosis. Eventually inflammation is followed by repair, with fibrin being laid
down.
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16. Clinico-anatomical types of necrosis: gangrene, decubitus, sequestration
Clinical forms of necrosis

Gangrene
Gangrene is the product of insufficient blood supply (ischemia) leading to hypoxia. It is
highest risks in those with Diabetes and long-term smoking. There are four types of
gangrene:
- Wet gangrene
- Liquitative necrosis
- Thriving bacteria in tissue
- Has poor prognosis due to sepsis
- Develops as product of blocked venous drainage (or rarely blocked arterial
supply)
- Skin appears soft, putrid, rotten and dark
- Dry gangrene
- Coagulative necrosis
- Often due to peripheral artery disease, but can be acute limb ischemia
- No infection
- Skin appears black, with sharp line of demarcation
- Noma (wet gangrene of exhausted children in cheeks and lips)
- Rapidly progressive, found in mouth or genitals of children
- Develops in the mucous membranes
- Product of bacterial pathogens (Fusobacterium necrophorum and Prevotella
intermedia)
- High mortality
- Gas gangrene (caused by gas forming gram +ve anaerobes)
- Caused by bacterial infection that produces gas within tissue (e.g Clostridium)
- Infection spreads rapidly
- Can cause necrosis, gas production and sepsis, progression to toxemia and
shock is rapid.
Decubitus ulcer (pressure sore)

This is damage to the skin and/or tissue overlying a bony prominence as a result of
consistent pressure and/or friction. Common sites include:
- Sacrum
- Coccyx
- Heels
- And hips
The consistent pressure to these sites restricts the blood flow to soft tissue, reducing tissue
tolerance for skin pressure and increasing risk of ulceration.
Such ulcers are more common in the elderly and bedridden.
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Sequestrum
A piece of dead bone that has become separated during the process of necrosis from
normal tissue. The pathological process is as follows:
- Infection in bone leading to intramedullary (inner most part of bone) pressure due to
inflammatory exudates (inflammatory fluids)
- Periosteum becomes stripped of ostium, leading to vascular thrombosis
- Bone necrosis due to lack of blood supply
- Sequestra formed
17. Hemorrhages - types, pathogenesis; denomination according to organ site

There are multiple ways of classifying hemorrhages, we’ll look at two of the easiest.
Firstly, what is a hemorrhage, simply put, hemorrhage is an escape of blood from a

ruptured blood vessel.
The neatest way to classify hemorrhages is based on the vessel that the blood has escaped
from:
- Arterial
- Bright red blood, pouring as a jet which rises and falls in time with pulse
- Protracted bleeding
- Venous
- Darker read, steady copious flow, blood loss is rapid when large veins opened
- Capillary
- Bright read, often rapid, but reduced volume, blood oozes
We can also classify the type of hemorrhage based on blood loss:

- Clas I
- 15% of blood volume, no change to vital signs
- Class II
- 15-30% of blood volume, patient tachycardic, skin may look pale and cool to
touch
- Class II
- 30-40% of blood volume, patients BP drops, HR increases, enters shock,
capillary refill worsens
- Class IV
- >40% of blood volume, limit of body’s compensation reached, death is near!
Where hemorrhage continues for too long, the body can go into hypovolemic shock,
leading to death. This is known as exsanguination.
Classifications of hemorrhage according to organ site are long and tedious, but hey ho, there
you go:
- Mouth
- Tooth eruption - losing a tooth
- Hematemesis - vomiting fresh blood
- Hemoptysis - coughing up blood from the lungs
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- Anus
- Melena - upper GI bleeding
- Hematochezia - lower GI bleeding
- Urinary tract
- Hematuria - blood in urine
- Head
- Intracranial hemorrhage - bleeding in skull
- Cerebral hemorrhage - bleeding in brain (subcat of ICH)
- Intracerebral hemorrhage - rupture of blood vessel within head
- Subarachnoid hemorrhage - blood in subarachnoid space
- Lungs
- Pulmonary hemorrhage
- Gynaecologic
- Vaginal bleeding
- Postpartum hemorrhage
- Breakthrough bleeding
- Ovarian bleeding
- GI
- Upper GI bleed
- Lower GI bleed
- Occult GI bleed
18. Hemodynamic disorders. Arterial hyperemia. Venous congestion - systemic

and organ-specific
Normal homeostatic control of fluid in the body ensures a balance between the intra, and
extracellular compartments of fluid (33% and 27% of body mass respectively). Where
this is disrupted, we can see some of the following conditions.
Edema
- Swelling
- Excessive accumulation of free fluid in the interstitial tissue spaces/serous cavities
- Free fluid in the peritoneal cavity is known as ascites
- Free fluid in pleural cavity is hydrothorax or pleural effusion
- While hydropericardium is fluid in the pericardium
- Etiology
- Increased hydrostatic pressure (impaired venous return)
- Reduced plasma oncotic pressure (reduction in proteins in plasma due to loss
or issue regarding synthesis)
- Lymphatic obstruction
- Sodium retention
- Inflammation (increased vascular permeability)
- Types classified by characteristics
- Pitting (high protein content in fluid)
- Product of vascular condition generally
- Non-pitting (low protein content in fluid)
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- Product of lymphatics generally

- Types classified by location
- Localised
- Generalised
- Fluid
- Fluids are classified as Transudates or Exudates
- Exudate is fluid that leads out of the capillaries due to inflammation
- Transudate is fluid pushed through capillary due to high hydrostatic
pressure (inflammation not required)
Arterial hyperemia
- Defined as increased blood in the arterial system
- Produced of increased inflow and vasodilation leading to engorgement with
oxygenated blood
- Happens normally in physiological processes
- E.g. exercise, blushing
- And pathological
- In infection
- Inflammatory process
- Increase in temperature and redness
- Is an active process
Congestion
- There are three types:
- Local
- Systemic
- Or Generalised
- Congestion is, simply put, the backing up of blood
- Passive process
- Below we will consider some examples of local and systemic congestion
Local
Obstruction of one part of the body, leading to build up of venous blood:
- Mesenteric venous occlusion
- Gross: Dark purple, thick walls, oedematous and haemorrhagic
- Torsion of testis/Ovaries
Systemic
This is the engorgement of systemic veins. It commonly leads to a pitting oedema, and can
be acute or chronic. In chronic cases we see chronic hypoxia potentially resulting in fibrosis.
Systemic congestion is the product of Left or Right sided heart failure, we’ll look at both, and
the implications of acute vs chronic congestions.
Left sided heart failure

- Acute
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- Result of acute failure of left ventricle, often a product of MI or Coronary

Artery disease
- As the left ventricle fails we see the build up of deoxygenated blood in the
lungs
- This buildup leads to pulmonary oedema and acute congestion of lung as
the additional hydrostatic pressure forces fluid into the lungs
- Gross structure sees heavy and moist lungs
- Microscopically, congested capillaries with fluid filling the alveolar spaces
- Chronic
- Also impacts the lungs, but this is a slower process
- Here we see chronic hypoxia in lung tissue, leading to fibrosis and
hemosiderin pigment being laid down.
- Gross morphology sees shrinking of lung, brownish colour
- Histologically we see the thickening of the alveolar wills due to the increased
hydrostatic pressure, the hemosiderin is visible, as are fibrous deposits
Right side heart failure

Most affected organ is the liver, and we see a massive pulmonary thromboembolism, with
secondary pulmonary disease
- Acute
- Acute congestion of the liver
- Distended central veins with sinusoids (vessels with larger gaps in
endothelium)
- Gross appearance of liver is slightly enlarged with a bluish hue
- Histologically, almost normal, but look for dilation of central veins
- Chronic
- Chronic liver congestion
- Central portions of the hepatic lobules are last to receive blood, and
therefore the first to atrophy. We can see the atrophy of these
hepatocytes leading to a nutmeg effect
- Gross morphology sees an enlarged and tender liver
- Chronic splenic congestion
- Right side heart failure also leads to chronic splenic congestion, this
sees additional firmness of the spleen, splenomegaly and cyanosis
- Microscopically - red pulp is enlarged, fibrous thickening of capsule
and some haemorrhaging overlying fibrous tissue
19. Systemic hemodynamic disorders - peripheral tissue hypoperfusion (shock).

DIC syndrome
So when we talk about Ischemia, we’re talking about decreased blood flow to a particular
tissue, which leads to tissue necrosis. Systemic hemodynamic disorder on the other hand
are those conditions that affect the whole body, not simply a part of it (as per above). Here,
we shall consider two types:
- Peripheral tissue hypoperfusion (shock)
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- Disseminated intravascular coagulation (DIC) syndrome
Peripheral tissue hypoperfusion (shock)

Simply put, shock is a decreased level of blood perfusion through a tissue (that is to say,
tissue doesn’t get enough blood).
This lack of blood perfusion generally a product of lack of blood pressure. Blood pressure
has two primary determinants:
- Vascular resistance to flow
- Cardiac output
- Heat Rate x Stroke volume
- (Stroke volume = End diastolic vol - End systolic vol))
So, any of these elements that make up blood pressure can be affected to reduce the blood
pressure and thereby trigger peripheral tissue hypoperfusion, we generally speaking
categorise shock into three categories:
- Hypovolemic shock (reduced blood volume)

- Non-hemorrhagic (i.e. result of dehydration)
- Hemorrhagic (from bleeding)
Here, reduced blood volume so reduced overall stroke volume, decreasing overall
pressure. This means less blood forced through the tissue capillaries. Key indicator is a
decrease in skin temperature, cold clammy to touch.
- Cardiogenic shock
Here, we see something has happened to the heart to reduce cardiac output, this may be
as a result of trauma, or Myocardial Infarction. In essence, reduced CO leads to reduced
blood pressure and reduced perfusion. Also shows decrease in skin temperature.
- Distributive shock (leakage of blood vessels and excessive vasodilation)

- Anaphylactic shock
- Neurogenic shock
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Here we see widespread vasodilation and vaso leakage in the peripheral vessels. This
leads to decreased vascular resistance and thereby decreased blood pressure and
decreased perfusion. Unlike the other two types of shock we are seeing an increase in blood
flow, but it’s just not under pressure, so less perfusion. This increase bloodflow means skin
temperature is warm to touch.
There general signs and symptoms of circulatory shock are:

- Low blood pressure
- Rapid heart rate (in an attempt to increase BP)
Clinical stages of shock

- Non-progressive
- Activation of compensatory mechanism allowing the vital organs to be
perfused
- The net effect is tachycardia and vasodilation with no damage to tissue
- Progressive
- The compensatory mechanism are not enough at this stage and we start to
see hypoperfusion with early ‘vital’ organ failure
- Oliguria (very small amounts of urine produced)
- Acidosis (anaerobic glycolysis occurs, increasing lactic acid, thereby
leading to lactic acidosis. This causes tissue and vessel damage)
- Irreversible
- Hemodynamic corrections are no longer of use, leading to severe cellular and
tissue damage
Pathology
The key conditions we see as a result of failure are:
- Multiple organ failure
- Subendocardial hemorrhage
- Acute tubular necrosis of kidneys
- Diffuse alveolar damage (shock lung)
- GI mucosal hemorrhages
- Liver necrosis
- DIC
DIC syndrome
Disseminated intravascular coagulation (DIC) syndrome is a pathological process
identified by widespread activation of the blood's clotting cascade, leading to the
formation of blood clots in the small blood vessels throughout the body.
These clots have two detrimental effects, firstly, and obviously, it can lead to multiple
ischemias throughout the body. Secondly, the clotting uses up platelets and clotting
factor, reducing the amount of platelets and clotting factor where needed elsewhere,
this means that any damage to vessel wall can lead to a bleed.
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To understand the etiology of this, it is important to remember a central tenant of clot

formation. The formation of new clots and the fibrinolytic processes are, in a healthy body in
balance. In some serious medical conditions, there is a release of procoagulants, which tip
the balance in favour of clot formation. These procoagulants may be Tissue Factor,
Bacterial or proteins. Diseases such as Malignancy, Obstetric events, Sepsis, Trauma or
intravascular hemolysis can all trigger the release of such procoagulants.
So, as mentioned, the consequences of this is widespread clotting, leading to ischemia, as

well as increased bleeding, as a result of reduced platelets and fibrinogen.
DIC is a secondary complication of various diseases, possible etiologies include:

- Obstetric complications
- Toxemia (infections such as sepsis or meningococcemia)
- Neoplasms
- Massive tissue injury (such as trauma or burns)
The prognosis for DIC is highly variable, largely based on the underlying disorder and the
severity of intravascular clotting and fibrinolysis. It can be Acute (such as caused by obstetric
complications) or Chronic (such as caused by cancer).
Treatment of DIC focuses on the treatment of the underlying disease, and the support of
organs affected by ischemia.
20. Thrombosis. Pathogenesis, thrombus morphology, types. Outcome of

thrombosis
Thrombosis is the formation of a blood clot (primarily platelets and fibrin) inside a blood
vessel, which obstructs the flow of the blood through the circulatory system.
Pathogenesis
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The pathogenesis of thrombosis is summed up by dear old Virchow, and his lovely triangle!
He described three factors that contribute to thrombosis:
- Hypercoagulability
- Hemodynamic changes (stasis and turbulence)
- Endothelial injury
Lets address the etiology of each in turn.
Hypercoagulability can be caused by genetic defects or

autoimmune disorders.
Hemodynamic changes can be the result of:

- Blood stagnation, possible causes include:
- Long periods of sedentary behaviour
- Heart failure
- Atrial fibrillation
- Cancers/malignancies
- Formation of intravascular plaques
Endoluminal injury can be the result of hypercholesterolemia, hypertension, smoking,

radiation, chemical irritation and others.
Thrombus morphology
Thrombi have a rough surface, due to more fibrin deposition, and are red or pale tan
based on the number of erythrocytes. Thrombi are attached to the vascular wall, this is in
contrast to post-mortem clots which are unattached.
Thrombi are made up of aggregated platelets and red blood cells, forming the plug, as
well as the cross-linked fibrin protein.
Types of Thrombi
- Arterial Thrombi
- Formed in the arteries
- Typically composed of platelet aggregates (white thrombus)
- Venous Thrombi
- Formed in the veins
- Largely composed of fibrin and RBCs (red thrombus)
Outcome of Thrombosis
- Propagation (increase in size)
- Embolization (see below)
- Dissolution (removed by fibrinolytic activity)
- Organization and recanalization
- This is the movement of the thrombus to the side of the vessel with the
formation of vessels through it.
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21. Embolism - arterial and venous; types, sites of origin, target organs
An embolism is a detached mass that is carried through the blood to a distant site.
More often than not, this is a thrombus that has become detached and then gotten lodged
somewhere in the pipes which can go on to form tissue ischemic necrosis.
Arterial Embolism
Depending on where the embolism enters the circulation, it can be arterial or venous. So, all
arterial thrombi would go on to become arterial emboli!
Arterial embolism can cause occlusion of any part of the body and is a major form of
infarction, and tissue necrosis. Embolisms in the brain or carotid artery can lead to
stroke, those that end up in the cardiac arteries can cause a myocardial infarction. As
well as affecting the brain, arterial embolisms commonly affect the lower extremities and
small bowl.
Risk factors include atrial fibrillation, mitral valve stenosis, age, hypertension and heart
failure, as well as prosthetic valves. In effect, anything that that fits Virchow's triad.
Venous Embolism
A venous embolism, originating from a systemic vein, on the other hand, will always impact
the lungs after passing through the right side of the heart, and cause a pulmonary
embolism. The most common sites of origin are the femoral veins.
Paradoxical embolisms are rare, and are those emboli that cross the veins to the arterial
blood system. These are only found in those where there are septal defects between the
atria or ventricles.
Types
As well as classifying Emboli as ‘Arterial’ or ‘Venous’, we can also classify them based on
the direction of the embolus:
- Anterograde - movement is in direction of blood flow
- Retrograde - movement is in the opposite direction of blood flow (usually venous)
We can also classify embolisms based on the thing that is doing the blocking, as it isn’t
always a thrombus on the move! Other types include:
- Fat emboli (generally a product of traumatic fracture of long bones)
- Air embolism (gas bubbles, either from decompression sickness or operative failure)
- Amniotic fluid (postpartum, result of tears in placenta or uterine veins)
- Neoplastic embolism (a bit of a tumour breaks off into blood stream)
Sites of origin
Arterial emboli most commonly originate in:
- Left atrium (following atrial fibrillation)
Venous emboli most commonly originate in:
- Femoral Veins
- Pelvic veins
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- Vena cava
- Deep veins of the calf
Target organs
As an embolus travels through the bloodstream it will eventually clog up a vessel. In some
cases this is a vessel that supplies an organ. If an embolus lodges itself an artery supplying
an organ, it will lead to a decreased supply of than organ, this is known as Ischemia. There
are two types;
- Absolute Ischemia - leading to infarction
- Relative Ischemia - leading to a decreased oxygen supply
- This can be acute or chronic
Where the embolus settles will go on to determine the nature of the infarction.
An infraction is an area of necrosis secondary to ischemia (decreased blood flow). They can
be:
- Red infarctions
- Occur in brain, lungs, liver and GI tract
- White infarctions
- Occur in heart, kidney and spleen, limited RBCs, mostly leukocytes and
platelets
- Septic infarctions
Infarctions can develop slowly or rapidly, when these occur rapidly there is a greater risk of
severe damage as the body is unable to compensate.
22. Edema - types, pathogenesis and pathomorphology according to organ site
Edema is the accumulation of extra interstitial fluid within tissues. It can also be in
cavities (e.g. pleural cavity = hydrothorax, pericardial cavity = pericardial effusion, peritoneal
cavity = ascites), we use the term Anasarca for severe generalized edema.
We divide edema into inflammatory and non-inflammatory causes. Fluid that causes
edema that is not due to inflammation is known as transudate, it has lower protein levels
(less than 1.012 specific gravity) because the vessel walls don’t usually let proteins through.
In contrast, exudate is when there is inflammation, during inflammation we have increased
vascular permeability, and as a result, proteins can escape.
Edema can also be pitting and non-pitting. Non pitting edema is caused by lymphedema
(blockage lymphatic vessels), Myxedema (advanced hypothyroidism) or lipedema.
Everything else is pitting.
Let’s look at some of the main types:

- Increased hydrostatic pressure
- May be due to impaired venous return, congestive heart failure, water
retention (hyperaldosteronism)
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- Pushes fluid out of the veins into the interstitium

- Reduced plasma osmotic pressure
- The body hates gradients, it compensates by letting more fluid out
- Lymphatic obstruction
- Less of an intake from lymphatic system causes fluid to build up in the tissues
- Water (and sodium) retention
- This reduces osmotic pressure in the vessels, as above, leading to more fluid
diffusing across
Edema can also be distinguished based on its location:

- Subcutaneous - often due to heart or liver
- Edema of loose connective tissue (e.e. Periorbital edema) - usually due to nephrotic
syndrome
- Pulmonary edema - normally due to left ventricular failure
- Brain edema - can be local (due to abscess or tumour) or general
23. Inflammation. Definition, etiology, pathogenesis, types

Inflammation is the body's response to harmful stimuli, such stimuli include:
- Mechanical damage
- Physical damage (e.g. Radiation, UV, Temperature)
- Chemical damage
- Biological damage (e.g. Viruses, bacteria)
Inflammation can be classified acute or chronic. Acute being the initial response, achieved
through plasma and leukocyte movement (especially neutrophil), while prolonged
inflammation is chronic, and tends towards a predominance of mononuclear cells, where
we observe simultaneous destruction and healing of the tissue.
There are three main stages of inflammation which can vary in intensity and duration, these
stages are:
- Vasodilation and increased vessel permeability
- First, very brief vasoconstriction followed by prolonged vasodilation
- This is a result of an increase histamine, kinins, prostaglandins and other
cytokines
- Phagocyte migration and phagocytosis
- Increase in permeability of vessels for plasma proteins
- Margination, Rolling, Adhesion and Diapedesis (transmigration into extra
cellular space) of neutrophils and plasma proteins (emigration)
- Chemotaxis (due to cytokines)
- Pus formation (more on these three stages in pathology document)
- Tissue repair and regeneration
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The clinical signs of inflammation are:

- Colour
- Heat
- Swelling
- Pain
- Impaired function
- Vascular changes
- And Phagocytosis
(note only the first four refer to the gross signs of inflammation, the others are physiological
or microscopic).
24. Inflammation. Inflammation mediators

There are two types of inflammatory mediators. Cell derived mediators, and plasma derived
mediators. We have tabulated the core ones below.
Cell derived mediators

Chemical Source Function
Histamine Mast cells and basophils Increase arteriole dilation and increased
venous permeability
Serotonin Platelets Increase arteriole dilation and increased

venous permeability
Lysosomal enzymes Neutrophils & Macrophages Enzymes that breakdown etiological substance
Prostaglandins Leukocytes, platelets, Cause vasodilation, fever and pain

Endothelial cells
Leukotrienes Leukocytes Mediate leukocyte adhesion and activation
Platelet activating Leukocytes & Endothelial cells Different sources different functions:
factor (PAF) - Mast cells/basophils - increased
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vascular permeability
- Neutrophils - leukocyte aggregation
- Monocyte - leukocyte adhesion
- Endothelium - leukocyte
priming/chemotaxis
- Platelets - platelet activation
Activated oxygen Leukocytes Attack etiological factor

species
Nitrous Oxide Macrophages Cause vasodilation
Cytokines Lymphocytes, Macrophages, Cytokine is just a general term for proteins

Endothelial cells important in signalling. Functions are vast
Tissue Necrotising Macrophages Induce fever, cytokine production, endothelial

Factor & Interleukin 1 gene regulation, chemotaxis, leukocyte
adherence, activation of fibroblasts as well as
systemic effects such as low appetite and
increased heart rate.
Plasma derived mediators

Name Produced by Function
Bradykinin & Kinin system Induces vasodilation, increased vascular permeability and
Kallidin induces pain
Factor XII Liver Inactive protein, activated by collagen, platelets or exposed

basement membrane. Activates Kinin system, fibrinolysis system
and coagulation system when activated.
Membrane Complement system Complex of C5b, C6, C7, C8 and C9 that inserts into bacterial
attack complex cell walls and causes lysis.
Plasmin Fibrinolysis system Breaks down fibrin clots, cleaves C3 and activates Factor XII
Thrombin Coagulation system Cleaves fibrinogen to produce fibrin which can help clot.
So, let's take a quick look at some of those systems that we’ve just mentioned.
Kinin system
- Mediated by bradykinin and kallidin, two vasodilators
- Plays a role in inflammation, blood pressure, coagulation and pain control
- In effect, Neutrophils release Kallikrein, this in turn converts Kininogens into Kinins.
- Kinins (such as bradykinin) then go on to act to:
- Stimulate complement system
- Promote vasodilation and increase capillary permeability
- Activate pain receptors
- Act as chemotaxins
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Complement system
This is the name we give to the biochemical cascade of the immune system that allows
the body to activate and immune response and organise its tools.
It consists of around 30 complement proteins in the blood, synthesized by the liver, they
augment the function of the immune system by opsonization, membrane attack complex
formation and enhancing inflammation.
Opsonization
- The coating of a pathogen with compliment proteins to make
phagocytosis by macrophages easier thanks to receptor binding
Membrane attack complex
- Create a membrane attack complex where a group of proteins make a holes
in the membrane of the pathogen
The proteins travel around the body in an inactive form, and only become activated when
they come into contact with a pathogen or are activated by other complement
proteins. The way in which a complement protein becomes active can be via a Classical,
Alternative or Lectin pathway.
All of these pathways help to split (cleave) the Complement 3 (C3) protein into C3a and
C3b. C3a assists within inflammation while C3b assists in Opsonization and the
formation of membrane attack complexes.
Classical pathway
- Initiated when Antibodies bind to Antigens. A C1 complex then binds to the
antibodies, forming the C4b2a complex.
- C4b2a complex then sits on surface of pathogen and splits C3 into C3a
and C3b through the alternative pathway (below)
Alternative pathway
- Picks up once C4b2a has been created by the Classical (or lectin) pathway.
- Forms C3bBb (C3 convertase) complex from C4b2a on surface of
pathogen
Fibrinolysis system
Fibrinolysis is a process that prevents blood clots from growing and becoming problematic,
i.e. it breaks down a fibrin clot. There are two types, aptly named primary and secondary
fibrinolysis. The primary type is a normal physiological process, the second is due to medical
or pathophysiological reasons.
The fibrinolytic system is mainly mediated by the enzyme plasmin which cuts the fibrin
mesh at various places, creating fragments which can be cleared by the body.
Plasminogen is first formed in the liver, and

forms part of a clot when formed. Tissue
plasminogen activator (t-PA) and urokinase
are slowly released by endothelium which in
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turn activate the Plasminogen (which is embedded within the clot) into Plasmin, an
enzyme.
The Plasmin in turn breaks down the Fibrin mesh which held the clot together. Once it
has completed its task, the Plasmin is inhibited by alpha1-antiplasmin and
alpha2-macroglobulin, along with thrombin-activatable fibrinolysis inhibitor, which
works to make the Fibrin more resistant to the Plasmin.
25. Acute inflammation. Morphologic patterns of acute inflammation, types of

inflammatory cells, tissue alterations
Acute inflammation is an inflammatory response which occurs over seconds to days (while
chronic is measured in weeks).
It is initiated by resident macrophages, dendritic cells, kupffer cells and mast cells,
which release inflammatory mediators (described above). This triggers the vasodilation
(leading to redness and heat) and increased permeability (which triggers edema). The
release of bradykinins increase the sensitivity to pain.
We have spoken above about the vessel dilation, cellular changes and leukocyte infiltration
of the interstitial space, here we are going to focus on certain morphological patterns of
acute inflammation.
- Serous inflammation
- Accumulation of thick, protein-free fluid from plasma (exudate) or mesothelial
cells (effusion)
- Blisters are one such example
- Typical of burning and viral infections (e.g. Herpes)
- Fibrinous inflammation
- Increase in vascular permeability is greater than in serous inflammation
- We have protein rich exudate which contains fibrin (and others)
- Accompanied by pro-coagulative stimulus and is characteristic of the lining of
body cavities (especially serous membranes)
- Hemorrhagic inflammation
- Characterised by extra vascularisation of blood, often combined with
finbrinoheamorraghy
- Examples include Epidemic hemorrhagic fever, Leptospirosis and Plague
- Suppurative inflammation
- Characterised by formation of pus. A cell rich exudate, typical of bacterial
infections.
- Induced vasodilation is so strong we see cellular fragments in extracellular
space
- If bacteria penetrates deep into organ, an abscess can be formed (an
example of liquefactive necrosis)
- Ulcer
- Damages to organ surface due to shedding of superficial necrotic tissue
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- Commonly found in mucosas of hollow organs (e.g. GI tract) and lower limbs
of those with circulatory diseases or diabetes
The cells predominantly involved in inflammation vary depending on the time frame:
- Neutrophils
- Dominate in the first 24 hours, but disappear quickly after this
- They respond more rapidly to chemokines than others, and attach more firmly
to adhesion molecules
- Monocytes
- Take over from Neutrophils after about 24 hours as the the predominating
leukocyte
Additionally, as discussed in the question above, Endothelial cells and platelets play a role in
mediating inflammation by producing inflammatory mediators (see above table).
26. Chronic inflammation. Etiology, types, morphology
Chronic inflammation is inflammation over a period of weeks, months or years. Typically

considered longer that 6 months. The main characteristics of chronic inflammation are:
- Infiltration with mononuclear cells (macrophages, lymphocytes, plasma cells)
- Destruction of tissue
- Angiogenesis and fibrosis in attempted tissue repair
The three main causes of chronic inflammation are:

- Persistent infection
- Immune-mediated inflammatory diseases
- Toxic agents
Chronic inflammation can be the end result of acute inflammation, or may arise from the
following:
- Persistent infections (e.g. Mycobacterium tuberculosis)
- Immune-mediated inflammatory diseases
- Prolonged exposure to toxic agents
Cells and mediators

- Macrophages
- Dominant cells of chronic inflammation
- Known as Monocytes in the blood, then move to the tissue as macrophages,
activated by diverse stimuli, either via classical or alternative activation
- Classical - induction by endotoxin from T cell derived signals, have
microbicidal actions and trigger inflammation
- Alternative - induction by cytokines other than IFN-gamma, result in
Tissue repair, fibrosis and anti-inflammatory effects
- Lymphocytes
- Activation of T and B cells
- B-lymphocytes - plasma cells produce antibodies
- T-cells - T Helpers, suppressors and Killers
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The interactions between these two classes of cells are shown below.
Granulomatous inflammation
- Distinctive inflammation with central area of necrosis, surrounded by activated
epithelioid macrophages and giant cells, with a peripheral accumulation of
lymphocytes.
- Occurs in three main settings
- Persistent T-cell response to certain microbes (e.g. in TB)
- Immune mediated inflammatory diseases (e.g. Chrons)
- Unknown etiology of Sarcoidosis
- Foreign bodies, such as splinters, forming so called foreign body granulomas
Based on this we can divide chronic inflammation into two distinct morphological patterns:
- Nongranulomatous (diffuse and nonspecific)
- Mononuclear infiltrates into interstitium of organs, results in fibrosis
- Example include chronic viral hepatitis, pyelonephritis and Glomerulonephritis
- Granulomatous inflammation
- Can be specific (e.g. TB, Syphilis, Leprosy) or nonspecific (e.g. Foreign body)
27. Specific inflammation in rheumatism, tuberculosis, sarcoidosis, syphilis.

Histological characteristics of granulomas.
Rheumatism
- Any disease marked by inflammation and pain to joints, muscles or fibrous tissue
- Types include
- Back pain
- Tendinitis/Bursitis
- Capsulitis
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- Neck pain
- Osteoarthritis
- Many are autoimmune, including
- Ankylosing spondylitis
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Gout
- Such autoimmune cases are a result of T-cell activation and chronic inflammation to
the joints and connective tissue.
- This leads to forming of granulation tissue around the tissue (in arthritis for example,
granulation tissue forms around the synovial lining)
Tuberculosis
- Caused by Mycobacterium tuberculosis
- Symptoms include fever, chills, night sweats, loss of appetite, weight loss and fatigue
with chest pain, and prolonged cough
- Example of granulomatous chronic inflammatory disease. Overactive T cells
stimulate B-lymphocytes and fibroblasts to form granulomas in the lung tissue.
- If bacteria get into blood stream they will spread throughout the body
- Generally latent, will not always become active
Sarcoidosis
- Unknown etiology possibly due to immune reaction thanks to infection or chemical.
- Is a systemic inflammatory disease than can affect any organ, or be asymptomatic,
common symptoms include fatigue, lack of energy and weight loss, along with joint
pain
- Granulomas are formed throughout the lungs, skin, lymph nodes, or indeed
anywhere else in the body. Depending on location of Sarcoidosis, symptoms will
differ.
- (see above question for details on granulomas)
Syphilis
- STD caused by Treponema pallidum
- Three stages
- Primary - skin ulceration with sores
- Secondary - diffuse rash involving palms of hands and soles of feet, with
sores in mouth or vagina
- Tertiary - soft growths throughout body, neurological and heart symptoms
- Also exists in a latent asymptomatic form
- Pathophysiology
- Each stage has specific factors which lead to specific symptoms but the
recurrent feature is endarteritis, inflammation of the inner lining of the
arteries.
- Bacteria bind to endothelium, triggering immune response, which then attack
the bacterium, inflammation the cell wall
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Histology of granulomas
- Epithelioid cells (activated macrophages which resemble epithelial cells) surround the
necrosis
- Surrounding the Epithelioid cells are Lymphocytes with Multinucleated giant
(langerhans) cells
28. Specific inflammation in leprosy, typhoid enteritis, mycoses and parasitic

infections. Microscopic & gross pathomorphology of organ site alterations
Leprosy
- Progressive infection caused by Mycobacterium leprae
- Affects peripheral nerves and skin
- Development of granulomas in skin, respiratory tract and nerves.
- Results in inability to feel pain, skin lesions
- Two subspecies of Mycobacterium produce the disease
- M. Leprae
- Dry, scaly skin lesions and damage to peripheral nerves
- M Lepromatosis
- Skin thickening, granulomas include histiocytes (unlike the normal
granulocytes of M. Leprae)
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Typhoid enteritis
- Caused by Salmonella typhi (spread by contaminated drinking water)
- Symptoms include high fever, weakness, abdominal pain, bloody diarrhea and
headaches
- Some people develop a rash
- Pathophysiology
- Bacterial proteins are transferred to enterocytes and M cells in the intestine
triggering inflammatory response with neutrophil recruitment and mucosal
damage
Mycoses
- Mycosis is a fungal infection, often caused by opportunistic fungi, manifested on
people who have a weakened immune system or are under steroid or antibiotic
treatment
- Classifications
- Superficial mycoses (outer layers of skin and hair)
- Cutaneous mycoses (extends deeper into epidermis)
- Subcutaneous mycoses (goes deeper still to involve dermis, subcutaneous
tissue, muscle and fascia)
- Systemic mycoses (throughout body, originating primary in lungs)
- Can be opportunistic or primary
Parasitic infections
Inflammatory bowel disease is an autoimmune disease which triggers inflammation of the GI
mucosa. The presence of parasitic worm Schistosoma can trigger such a condition.
Some parasites also trigger granulosis, these include:

- Schistosomiasis
- These parasitic worms lay eggs and secrete proteolytic enzymes in the
bladder and intestines. These cause eosinophilic inflammatory reaction
- Toxoplasmosis
- Granulomas found in lymph nodes
29. Immunity. Types of immunity. Pathological immune reactions.

Pathomorphology
Immunity is the state of an organism having the biological defenses to fight a disease.
Immunity consists of the innate and adaptive immune system, these elements are nicely
summed up below:
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So, immunity can be innate or acquired, lets look at both.
Innate immunity
Innate (or nonspecific) immunity are the elements of the immune system that deal with
pathogens non-specifically and are elements we are born with. These include external
barricades such as skin and mucous membranes as well as internal defenses such as
phagocytes, antimicrobial proteins and killer (NK) cells.
Unlike the adaptive immune system it does not confer long-lasting immunity to the host.
Barriers of non-specific immunity

The key barriers are that of skin and mucous membranes (barriers that line open cavities
such as the nasopharynx and respiratory airways). There are also additional defense
mechanisms such as sweating on the skin and tears in eyes that help to provide defense.
The gastrointestinal tract includes elements such bile acid and gut flora that assist
immunity.
Phagocytes
Phagocytes can be divided into two categories, Neutrophils and Macrophages ( free and
fixed respectively).
Neutrophils
- Are formed from stem cells in bone marrow, most abundant form of white blood cell
- Short-lived, highly motile and can enter parts of the tissue where other cells can’t
- Phagocytic, nucleus divided into 2-5 lobes.
- They operate at the beginning phase of inflammation often as a result of bacterial
infection, migrating through blood vessels.
- They are the predominant cells in pus
Macrophages
- Large phagocytes, digesting pathogens as a secondary defense to neutrophils.
- Found in all tissues, p atrolling for pathogens through amoeboid (crawling)
movement - we call them different things in different tissues
- Do not get destroyed after phagocytosis, unlike neutrophils.
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Steps of phagocytosis
- Phagosome region is formed to ingest pathogen into cell
- Fusion of lysosomes with phagosome creates a phagosome
- Waste material then expelled
NK Cells
Natural killer cells are cytotoxic lymphocytes, central to the Innate immune system. They
are responsible for dealing with viral-infected cells.
All healthy cells have a protein called MHC on their surface, when a cell is infected by a virus
the MHC (Major Histocompatibility Complex) is damaged and triggers cytokine release,
causing lysis or apoptosis.
NK cells differentiate and mature in the bone marrow, lymph nodes, thymus and others.
The complement system and Inflammation are also both important aspects of the innate
immune system.
Adaptive immunity
Adaptive (acquired) immunity is our learned immunity. Adaptive immunity is carried out by
two different lymphocytes, B cells and T cells.
B cells are activated to secrete antibodies. These are immunoglobulin proteins which
travel through the bloodstream and bind to antigens causing it to inactivate, more in this
later.
T cells are a group of lymphocytes that induce the death of cells that are infected with
pathogens (similar to Natural Killer cells, but more specific).
Humoral immunity
Adaptive immunity can be broken down into two types, Humoral and Cell mediated.
Humoral immunity is immunity mediated by macromolecules in extracellular fluids
(humours). This includes antibodies a nd complement proteins. Cell immunity looks at the
immune response that does not involve antigens but rather phagocytes and
T-lymphocytes, i.e. cells are doing the dirty work, not macromolecules.
Structure of Antibodies
Antibodies are large Y shaped glycoproteins called
immunoglobulins. Each antibody consists of four polypeptide
chains - two heavy chains and two light chains. These chains
are connected by disulfide bonds and consist of structural
domains (see protein structure). There are five different types of
Immunoglobulin heavy chain, these help us divide the antibodies
into IgA, IgD, IgE, IgG and IgM antibodies.
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The ‘tip’ of the Y forms the antigen binding sites, these are highly variable and consist of
110-130 amino acids, giving the antibody its specific bonding capabilities.
Pathological forms of immune reactions.
This question is asking about hypersensitivity disorders and Autoimmune responses.
There are four hypersensitivity reactions, Types I-IV

- Type I - immediate hypersensitivity
- Type II - cytotoxic reaction
- Type III - Immune complex disorder
- Type IV - Delayed/T-cell mediated hypersensitivity
Autoimmunity is the ability of the immune system to identify its own healthy cells. A disease
in this part of the immune system is known as an ‘autoimmune disease’ and leads to the
cells of the immune system destroying healthy cells.
In order to ensure the body is able to identify healthy tissue not to attack it, the body must
ensure its immune cells are ‘Tolerant’ to normal cells. Its mechanism for doing this is
divided into Central and Peripheral Tolerance.
Autoimmune diseases can be Systemic or Local, we will look at some examples below:
- Systemic
- Systemic Lupus erythematosus
- Genetic basis, Type III chronic hypersensitivity to self
- Immune system attacks joints, red blood cells, skin, and more
- Rheumatoid arthritis
- Chronic inflammatory disease attacking joints causing synovitis
- Also damages skin, heart, blood vessels and lungs
- TNF plays central role with T-cell reaction
- Local
- Hashimoto thyroiditis
- Autoimmune attack against thyroid leads to hypothyroidism
- Multiple sclerosis
- Immune system attacks the myelin sheath of the nerves
30. Transplantation immunity. Rejection of tissue transplants
Transplant immunity
When organs are transplanted into the body the immune system recognises this as foreign
prompting an immune response.
The thing that actually causes the rejection in transplants is the differing MHC molecules
on the donated organ to that of the patient. MHC molecules are codominantly
expressed and inherited as haplotypes (one from each parent), this makes each person
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half identical to each parent, and only 25% likely to have a sibling with the same MHC
genetic coding.
Rejection is an adaptive immune response via cellular immunity (killer T-cells) as well as
humoral immunity (activated B-cells secreting antibodies).
There are two rejection pathways, direct and indirect.
Direct rejection (cells) pathway:

- CD8+ T-cells identify foreign MHCI and activate to become killer T-cells which
then start killing the transplant
Indirect (Antibodies)
- CD4+ T-cells identify foreign MHCI and activate releasing cytokines prompting
B-lymphocytes to start releasing antibodies against the transplanted organ.
Graft vs Host
This is the term given to when the host of a tissue donor rejects the tissue (via the
mechanism explained below).
The symptoms include damage the to grafted tissue (and its associated function) along with
damage to the liver, skin, mucosa and Gastrointestinal tract (basically secondary lymphatic
systems) as well primary lymphatic systems of bone marrow and thymus.
Rejection can be acute or chronic depending on if it is in the first 100 days or later.
Types of transplant
Transplants can be:
- Autograft
- Tissue comes from the patient themselves
- Allograft
- Transplant of an organ or tissue between genetically non-identical members
of the same species
- Isograft
- Subset of allograft, where tissue is transplanted from a genetically identical
individual (identical twin)
- Xenograft
- Transplant from another species (e.g. pig heart valves)
- Split transplants
- Organ split and divided between two individuals (e.g. liver between adult and
child)
- Domino transplant
- In those with cystic fibrosis where both lungs need to be transplanted it is
easier to also replace the heart. As the heart is technically still healthy this is
then donated to another.
There are three types of Transplant rejection:
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- Hyperacute
- Caused by blood type incompatibility (Type II hypersensitivity, immediate)
- Acute
- T-cell mediated immune response against foreign MHC, occurs in weeks to
months.
- Chronic
- T-cell mediated process in which the foreign MHC looks like a self MHC
carrying an antigen, slower than Acute reaction
31. Regeneration and repair: types of physiologic renewal and posttraumatic repair
in different cells and organs
Following a traumatic incident, there are two possible outcomes, cellular regeneration or
fibrosis (scarring). These two components are defined as Tissue Healing.
Regeneration - Not al tissues can regenerate, there are three classes of cells differentiated
based on their regenerative capacities:
- Labile cells (stem cell) regenerate throughout life e.g. skin, mucosal lining
- Stable cells (stem cells and differentiated cells) which replicate at low levels. E.g.
Hepatocytes
- Permanent cells (differentiated cells with few stem cells) are not able to regenerate.
E.g. neurons and cardiac muscle
Fibrosis (and remodelling) - replaces tissue with connective fibrous tissue.

- Fibrosis is predominantly mediated by TGF-beta (Transforming Growth Factor beta),
Fibroblast growth factor, tumor necrosis factor and vascular endothelial growth factor.
- These factors form Granulation tissue is formed with active fibroblasts and capillary
proliferation which lays down collagen type 3
- This produces a scar made of collagen type 1, with wound contraction mediated by
myofibroblasts
Types of wound healing

- Category 1
- Also known as healing by first intention, occurs within hours as a result of a
surgical incision where there is minimal cellular damage and the sound is
sewn together.
- Category 2
- Where wound edges are not sewn together, can be called delayed primary.
Phagocytosis of contaminated tissues occurs along with epithelization,
collagen deposition and maturation.
- Category 3
- Also known as healing by secondary intention, in this case there is a more
intense inflammatory process and a larger quantity of granulomatous tissue is
formed, with a more significant scar.
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32. Regeneration and repair: wound and bone healing. Stages of the reparative
process.
See above for definitions of regeneration and repair.
Bone healing
The phases of bone healing are:
- Reactive phase
- Fracture and inflammatory phase
- Granulation tissue formation
- Reparative phase
- Cartilage callus formation - this bridges the gap in broken bone
- Lamellar bone deposition - bone replaces the cartilage cap (endochondral
ossification)
- Remodelling phase
- Remodeling bone to original contour - lamellar bone replaced with compact
bone
Stages of wound healing process

- Hemostasis
- Following initial injury there is an outflow of blood and lymph. This activates
clotting mechanisms with instant vasoconstriction followed by
vasodilation. This vasodilation allows for the movement of lymphocytes and
other cells into the interstitial.
- Vasoconstriction is mediated by thromboxanes and prostaglandins released
from the endothelium, with vasodilation being predominantly mediated by
histamine released by mast cells.
- Inflammatory phase
- With vasodilation there is an influx of fluid into the interstitial. Within an
hour of wounding neutrophils are in the wound region, helping to kill
bacteria. This is along with T-helper cells releasing cytokines to activate
cellular immunity.
- After a few days, neutrophils die off, and macrophages begin to
dominate. These help to mediate the early stages of proliferation.
- Proliferative (Granulation) phase
- 2-3 days after the wound occurs, fibroblasts enter the wound and begin the
proliferative phase. This begins with two distinct processes, angiogenesis,
the vasculation of the region, mediated by vascular endothelial growth factor,
and fibroplasia and granulation formation, mediated by fibroblasts,
stimulated by TGF-beta and Platelet Derived Growth Factor.
- Once the granulation tissue has been laid down, reepithelialization can
occur. Basal keratinocytes are the main cells responsible for the laying down
of such cells.
- As reepithelialization occurs the wound undergoes contraction, this is a key
figure in wound healing and is marked by the laying down of actin from
myofibroblasts which help to pull the edges of the wound together.
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- Remodelling (maturation) phase

- As collagen formation and degredation equalise the maturation phase is
said to have begun. Type III collagen is now replaced by type I collagen,
and the strength of the scar is massively increased. This sage can occur for
as long as year.
33. Adaptations: hypertrophy, hyperplasia and metaplasia. Microscopic & gross

pathomorphology
Once a cell experiences stress it will try to adapt. Hypertrophy,

hyperplasia and metaplasia are all types of cellular adaptation.
Hypertrophy
- Increased cellular size.
- If occurs in a high enough percentage of an organs cells, the
entire cell will increase in size.
- Heart and kidney are of particular risk to such modification
- Microscopically, there is no change in the number of cells,
only the size is increased.
Hyperplasia
- Increased cell number as a result of increased mitosis
- Can be physiological (compensatory and hormonal) or pathogenic
- Most common in epidermis, intestine, liver and bone marrow
- Size of organ will increase macroscopically, microscopically, we’ll
see an increased number.
Metaplasia
- Once cell type is replaced with another
- A reversible processes, commonly occurs in respiratory tract in
response to inhalation of irritants (bronchial cells convert from
ciliated columnar to non-ciliated squamous)
- Morphological changes in this case would include seemingly
swollen respiratory tract. Microscopic morphology shows a change
in cellular type. (image shows metaplastic epithelium, converting
simple columnar (left) to squamous (right).
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34. Adaptations: atrophy. Types of atrophy. Microscopic and gross

pathomorphology
Cellular atrophy is a decrease in cell size. If enough cells decrease in size then the whole
organ will decrease. Some examples include the natural process in the thymus, skeletal
muscle atrophy as well as the brain.
Types of atrophy are:

- Muscle atrophies
- Disuse
- Dystrophies and motor neuron conditions
- Atrophy of muscles caused by damage to motor nerves, or muscle tissue
itself. Examples include Charcot-Marie-Tooth, all other Muscular Dystrophies.
Atrophies of the brain tissue is a common disease which affects the brain, it
can be generalised or localised, and while some degree of atrophy is natural
with age, severe atrophy can lead to disorders such as Alzheimer's.
- Gland atrophies
- Adrenal gland atrophy occurs during prolonged steroid abuse, atrophy of
breasts can occur following estrogen reduction.
- Vaginal atrophy
- In postmenopausal women, walls of the vagina become thinner
Some types of atrophy are physiologically normal, such as the shrinking of the thymus
throughout one's life. Additionally, atrophy can be full body atrophy in cases of severe
malnutrition.
The mechanism of atrophy is a combination of decreased protein synthesis and increased

protein degradation. In many circumstances, atrophy is combined with autophagy,
decreasing the number of cells as well as the size.
35. Neoplasia: etiology, pathogenesis, classification and nomenclature
A neoplasm is an abnormal mass of tissue, the growth of which is not physiologically

normal and occurs as a result of cell division without control.
Given we have just studied hyperplasia, an increased cell number as an adaptive response,
the question could be asked, how does a neoplasm differ from hyperplasia. Simply put, a
neoplasm is the proliferation of a single cell, while hyperplasia is many cells
undergoing cellular division, creating a heterogeneous cellular collection (polyclonal).
Etiology
In order for uncontrolled cell proliferation, we need a genetic mutation which will affect one of
the following:
- Encoding of the cyclins or CDKs (responsible for controlling the cell cycle
checkpoints)
- Encoding of the proteins that respond to these complexes
- Encoding of the regulation of these complexes
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- Encoding of growth factors/mitogens (mitogens relieve negative controls)

- External growth factor receptors
- Tumour suppressor genes
We call genes that code for the above (i.e. genes with the potential to cause cancer)
proto-oncogenes. As and when they mutate (if they do), causing variation of function, they
become oncogenes. Damage to these genes can be as a result of exposure to external
carcinogens, or simply internal DNA damage (such as ROS damage).
One such important gene is TP53, a monitor of stress in the cell and involved in DNA repair,
cellular senescence and apoptosis. Damage to this gene is one of the leading causes of
cancer.
Pathogenesis
Damage to proto-oncogenes predisposes the individual to the proliferation of cells
without adequate controls, this may be as a result of not responding appropriately to
growth factors, or alternatively cell cycle checkpoints not successfully holding the cycle. This
causes uncontrollable cellular reproduction.
Classifications
Neoplasia can be benign or malignant, let us consider the key features of the two:
- Benign
- Well differentiated
- Slow growth
- Cohesive
- Expansile
- Capsule
- No invasion/infiltration
- Malignant
- Poorly differentiated
- Rapid growth
- Non-cohesive
- No capsule
- Invasion
- Metastasis
Nomenclature
Cell of origin + oma (benign) or, where malignant sarcoma (if of mesenchymal origin),
carcinoma (if of epithelial origin)
- Glandular Epithelium
- Adenoma or Adenocarcinoma
- Fibroblasts
- Fibroma or Fibrosarcoma
- Osteoblast
- Osteoma or Osteosarcoma
- Lipocyte
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- Lipoma or Liposarcoma
A tumour is considered benign when its characteristics imply it will remain localized.
36. Neoplastic growth, histogenesis and structure characteristics. Precancer.

General histological features of benign, malignant; epithelial and mesenchymal
tumours.
There are a number of characteristic features of neoplastic growth that we shall consider
here:
- Failure of contact inhibition
- Normal cells will stop cellular proliferation when they bump against other cells,
this is not the case in cancer cells. The failure of this is thought to relate to the
tumor suppressor gene NF2 which codes for cadherins, which mediate
contact inhibition.
- Evasion of cell death
- There are two apoptotic pathways, extrinsic (where the TNF receptor is
externally activated) and the intrinsic mitochondrial pathway.
- Within these pathways, cancer cells have the opportunity to disrupt in a
number of ways, the most commonly cited is the mutation of BCL2 gene,
causing overexpression of BCL2 protein, protecting a cell from apoptosis.
- Limitless replicative potential
- Most cells have cellular senescence, a replication limit due to the progressive
shortening of telomeres.
- The short telomeres are generally picked up by cellular checkpoints, in a
cancer cell, where the checkpoints are non-functioning, we see a limitless
level of cellular reproduction.
- Sustained Angiogenesis
- Cancer cells have increased metabolic needs, as such, they need a strong
blood supply. They get this by triggering angiogenesis through the actions of
HIF-1 alpha (hypoxia-inducible factor 1 alpha), an oxygen sensitive
transcription factor. This triggers transcription of the proangiogenic factor
VEGF.
- Ability to Metastasize
- Malignant neoplasms are able to metastasize, that is to say, the spread
through the bodies blood or lymphatic system to form secondary
metastatic tumours. The process for doing so is as follows:
- Cancer cells begin by loosening intercellular junctions between
them
- Then they trigger degradation of the type IV collagen in the ECM
- They then attach to the basal membrane
- Finally they migrate through the basal membrane and into the
bloodstream.
- From here they are able to form a tumor cell embolus, and go on
to adhere to the basement membrane elsewhere.
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- They then undergo extravasation and the metastatic tumour beings to

take root.
- Evasion of the immune system
- Cancerous cells are able to avoid the immune system by a number of
different features, not only does their DNA alter, creating a genetically
heterogeneous structure but they are also able to directly deactivate T-cells.
For instance PDL1 probe on the cancer cell binds to a PD1 receptor on the
T-cell making it inactive
Precancer
Precancerous conditions are states in which the morphology of a cell is associated with an
increased risk of cancer. Examples include dysplasia (abnormal epithelial development)
and benign neoplasm. Such cells appear abnormal under microscopic investigation and if
swiftly identified and removed and help to prevent cancer (think cervical screening for
cervical intraepithelial neoplasia (CIN)).
Benign, Malignant, Epithelial and Mesenchymal tumours

- Benign
- Well differentiated
- Slow growth
- Cohesive
- Expansile
- Capsule
- No invasion/infiltration
- Malignant
- Poorly differentiated
- Rapid growth
- Non-cohesive
- No capsule
- Invasion
- Metastasis
- Epithelial (Carcinoma)
- Benign
- May be papilloma or adenoma tye
- Papilloma appear in stratified squamous epithelium, urothelium
and galactophorous ducts
- Adenomas are tumours of glandular epithelium and mucosa of
hollow organs.
- Examples include squamous cell papilloma (skin),
adenomatous tubulovillous polyp and fibroadenoma of the
breast
- Malignant
- Most common type, for morphology see rules regarding malignant
tumours.
- Staging refers to the physical/clinical manifestation of the cancer, which
expresses the extent of invasion and metastasis, stages from I - III
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- Mesenchymal tumours (Sarcomas)

- Relatively rare (tumours made of bone, cartilage, fat, muscle etc).
- Graded (low, intermediate or high) based on subcellular characteristics which
imply the aggressive nature of the cancer. Higher grade tumours more likely
to undergo metastasis.
37. Connective tissue benign & malignant neoplasms. Microscopic & gross
pathomorphology
Benign connective tissue tumours

Such tumours originate from the connective tissue (fibrous, adipose tissues), the most
common examples are lipoma, hemangioma, leiomyoma, chondroma and osteoma.
- Chondroma
- Tumour cells are chondrocytes and resemble normal cells which produce
cartilaginous matrix. There is a vascular axes within the tumour which
differentiates it from normal hyaline cartilage
- Cavernous hemangioma (liver)
- Endothelial proliferation, tumour has large cavernous spaces, lined by
endothelial cells, the spaces are connected by fibrous tissues.
Malignant connective tissue tumors

Known as sarcomas. Mostly diagnosed in the young.
- Fibrosarcoma
- Originates from fibroblasts. Cells are arranged in short fascicles which split
and merge, making it look like a fish bone. Poorly differentiated tumors
have more atypical, giant, multinucleated cells with reduced collagen
production.
- Osteosarcoma
- Tumour cells present osteoblastic differentiation. Highly anaplastic, some
are giant and present atypical mitotic figures. Cells are irregular in
structure and form, included in an osteoid matrix, possibly with cartilage and
vessels.
38. Benign & malignant neoplasms of smooth and striated muscle. Microscopic &
gross pathomorphology
Skeletal muscle neoplasms

- Almost all malignant, Rhabdomyoma (benign type) is rare, often found in the heart
- Rhabdomyosarcoma is the most common neplasia, appearing before the age of
20, found in head and neck.
- Histologically classified into embryonal, alveolar and pleomorphic
- Identified by rhabdomyoblast cells found in the neoplasm, they are tadpole in
shape.
Smooth muscle neoplasia
- Leiomyomas are benign smooth muscle tumours and are quite common. They can
be found in any smooth muscle but most commonly in the uterus.
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- Asymptomatic, large swellings appear on uterine section.

- Microscopic appearance shows bundles of normal looking smooth muscle
cells
- Leiomyosarcomas are malignant, occurring more commonly in females than males
in the skin of deep soft tissues and extremities.
- These manifest as large painless masses. Histological examination shows
spindle cells with cigar shaped nuclei.
39. Benign & malignant neoplasms of vessel walls
Benign vascular tumours:

- Hemangioma
- 7% of all benign tumours
- Focussed on head or neck, nearly ⅓ found in liver.
- Variants include capillary (comprised of capillarys), juvenile and cavernous
hemangiomas (dilated vascular channels, spaces divided by stroma) as well
as pyogenic granulomas (comprised of granulation tissue, often bleed and
ulcer).
- Lymphangioma
- Lymphatic counterpart of hemangiomas
- Simple and carvounes form. Simple is found in head and neck, comprised of
networks of endothelium lined spaces. Cavernous comprised of massively
dilated lymphatic spaces separated by connective tissue stroma.
Malignant neoplasms:
- Angiosarcoma (Hemangiosarcoma)
- Malignant endothelial neoplasms.
- Start small, sharply demarcated asymptomatic red dots, then increase in size
and become gray-white masses.
- Microscopic examination shows ranging differentiation, some are clearly
endothelial while others are much more generic.
- Hemangiopericytomas
- Derived from pericytes that surround the capillaries. Very very rare
- Kaposi sarcoma
- Caused by Kaposi sarcoma herpesvirus, most common in patients with AIDS
- Can be classic, endemic african or transplantation associated
- Has three stages, patch, plaque and nodule lesion.
40. Osteogenic sarcoma. Malignant synovioma. Anatomic sites, microscopic &

gross pathomorphology.
Primary bone tumors are rare, secondary metastatic bone tumors are more common. Here
we’ll take a look at some:
- Benign
- Osteoma - facial bones and skull
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-Histologically similar to normal bone, bony protrusion on bones

surface
- Osteoid osteoma - metaphysis of femur and tibia
- Histologic pattern of interlacing trabeculae of woven bone. Often arise
beneath the periosteum. Morphologically look like lesions.
- Osteoblastoma - vertebrae
- Morphologically and histologically similar to osteoid osteoma
- Malignant
- Primary osteosarcoma - metaphysis of distal femur, proximal tibia and
humerus
- Malignant osteocytes forming osteoid, possibly with cartilage
- Gross appearance shows gritty gray-white tumors, tumor cells are
very heteromorphic and hyperchromatic nuclei with giant cells.
- Secondary osteosarcoma - femur, humerus and pelvis
- Histologically the same as primary osteosarcoma
Malignant synovioma
A malignant synovioma (or synovial sarcoma) is form of cancer that occurs in close
proximity to the joint capsules, it is a soft tissue sarcoma.
Most commonly occurs near large joints of arm and leg, but can be found in other
locations. Histology shows two cell types, a fibrous spindle cell, and an epithelial like cell.
Generally both cells appear.
Most malignant synovioma are a result of genetic mutation t(x18).
41. Benign & malignant neoplasms originating from melanocytes. Anatomic sites,
microscopic & gross pathomorphology
There are three melanocytic proliferations we will consider:

- Melanocytic Nevi (benign neoplasm)
- Derived from melanocytes, brown, uniformly pigmented with defined borders
and papules.
- Nuclei are uniform and round, with low mitotic activity. Only have a cosmic
concern
- Found on skin where there is high sun exposure
- Dysplastic nevus
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- Can be sporadic or familial, familial more likely to become malignant.

- Larger and may number in their hundreds. Flat macules raised slightly with
pebbly surface and irregular borders.
- Microscopically, show evidence of abnormal growth, with cells replacing
the normal basal cell layer and alterations to the surrounding dermis.
- Found in areas on all areas of skin and increase risk of melanoma.
- Melanoma
- Malignant melanocyte growth, intimately linked to sunlight exposure.
- Large variation in pigment, shades of black, grown, red, blue and grey
observed. Borders are irregular and notched
- Microscopically, cells grow as poorly formed nests, with vertical and
horizontal growth. Metastatic risk increases with increased vertical
growth.
42. Teratogenous neoplasms - teratomas and teratocarcinomas. Anatomic sites,

microscopic & gross pathomorphology
A teratoma is a tumor made of different types of tissue (e.g. bone, hair, dermal,
cartilaginous, neural), commonly forming in ovaries, testicles or tailbone. A teratoma is a
type of germ cell tumor, and can be classified as mature (generally benign) and immature
(may be malignant), we can determine the nature of the teratoma based on histology.
Mature teratomas
- Mature tissues derived from all three germ cell layers (ectoderm, endoderm and
mesoderm)
- Usually contain cysts lined by epidermis with dermal appendages (e.g.
hair follicles), so known as dermoid cysts
- Commonly found in ovaries, mostly unilateral up to about 10 cm in diameter. About
1% become malignant, generally however, asymptomatic.
Immature Teratomas
- Found early in life, average age 18. They are bulky and predominantly solid
(unlike mature teratomas which are cystic).
- Microscopic examination shows immature tissues, minimally differentiated.
- Often ovarian or testicular, solid on examination
- Generally malignant and can form metastases
43. Congenital anomalies. Classification. Exogenous and endogenous teratogens.
Congenital anomalies are structural defects that are present at birth, although some only
become apparent later. The etiology of such anomalies is listed below:
- Genetic
- Chromosomal aberrations
- Mendelian inheritance
- Environmental
- Infections
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- Maternal diseases
- Drugs and chemicals
- Multifactorial
We generally categorise congenital anomalies as either structural or functional
(metabolic).
- Structural
- Polydactyly
- Syndactyly
- Cleft lip (with or without cleft palate)
- Cyclopedia
- Microcephaly
- Functional
- Glucose-6-Phosphate dehydrogenase deficiency
- Galactose Kinase deficiency
- Phenylketonuria
Regarding exogenous and endogenous teratogens, a teratogen is a substance which

causes a fetus to mutate (from the greek tera meaning monster). Exogenous substances
include Alcohol, Folic acid antagonists, Androgens, phenytoin, Thalidomide, Warfarin,
13- cis retinoic acid and others. Endogenous factors are hereditary, and pertain to single
gene inherited disorders (e.g. PKU), multigenic factors (Diabetes) or chromosomal
abnormalities (Trisomy 21, Downs).
44. Gene mutations. Chromosomal syndromes and diseases. Blastopathies -

double malformations.
A gene mutation is the permanent alteration in DNA sequence that makes up a gene. There
are two main classifications:
- Hereditary (inherited from a parent, affecting every cell, also known as germline
mutations)
- Acquired (or Somatic) that occur at some point in the person's life, can be an error in
DNA replication or repair
Mutations can affect single genes, or the chromosomes themselves, types of genetic
mutation are:
- Missense - wrong protein coded for
- Nonsense - stop codon coded for
- Insertion/micro deletion- frameshift mutations
- Micro Duplication
- Repeat expansion
Alternatively, we can have structural chromosomal mutations, also known as structural

mutations, these are errors on a chromosomal level rather than a simple base pair level:
- Deletion
- Duplication
- Inversion
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- Translocation
Humans are also susceptible to chromosomal aneuploidy, this is where the total number of
chromosomes is not the normal 46. Where we see Trisomy (e.g. Trisomy 8, 9, 13, 18 or 21)
we get 47 chromosomes, and where we have Monosomy (e.g. Monosomy X - Turner
syndrome) we have 45 chromosomes. These result in structural and functional errors in fetal
development.
Blastopathy
Blastopathies occur during the first 15 days following fertilisation. The most frequent cause is
a chromosomal aberration in combination with environmental factors. The effects can be
varied:
- Superficial or deep implantation of blastocyst in uterine wall
- Disturbance of embryo orientation
- Empty embryo sacs
- Double malformation????/ Unknown - anybody able to shed some light here?
45. Embryopathies. Cardiovascular system malformations
Embryopathies occur within the period of 16-75 days following fertilisation. Congenital
heart diseases account for 20-30% of all birth defect.
Most diseases arise from faulty embryogenesis during weeks 3-8 when most
cardiovascular structures develop. Causes are often environmental, teratogens and
genetic factors. The formation of the cardiovascular system is a complex series of steps with
multiple genes involved, including Wnt factor, vascular endothelial growth factor, bone
morphogenetic protein, transforming growth factor beta, fibroblast growth factor and notch
pathways. The miscoding of any of these factors will cause CVS errors.
Malformations are divided into three categories based on their properties:

1. Malformations causing left to right shunt
2. Malformations causing right to left shunt
3. Malformations causing obstruction
Left to right shunt

- Results in increased pulmonary blood flow. Such exposure of the low-pressure,
low-resistance pulmonary circulation to the increased pressures and volumes of the
left to right shunt causes lung vasculature to increase resistance in an attempt to
protect itself, which in turn resulting in right ventricular hypertrophy and
eventually failure
- These are the most common type of malformation and include
- Atrial septal defects (where foramen ovale does not close)
- Ventricular septal defects
- Patent ductus arteriosus
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Right to left shunt

- Causes cyanosis as a result of decreased pulmonary circulation
- This decreased pulmonary circulation causes decreased blood oxygen levels
Obstruct vascular flow

- Narrowing of the chambers, valves or major blood vessels
- Generally increases peripheral blood pressure and depending on the extent of
obstruction can cause ischemia
46. Embryopathies. Malformations of central nervous system and limbs.
Congenital abnormalities of the CNS can be divided into developmental malformations

and disruptions.
Developmental malformations are the result of flawed brain development. This may be
genetic or environmental. Disruptions result from destruction of normally developed (or
developing) brain and are environmental or intrinsic (e.g. fetal infection).
Holoprosencephaly, where the forebrain is not divided into hemispheres, is an
example of a malformation while hydranencephaly, where there are fluid filled sacs
reducing brain mass is a disruption.
The CNS is particularly sensitive to teratogenic factors, and external environmental factors
will often result in CNS damage before other forms of congenital malformation.
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Common neurological embryopathy occur within the neural tube, which develops from the
neural plate at around the 25-26 day. For instance, defective closing of the neural tube
results in brain defects or spina bifida, depending on if it is the top or bottom that fails to
close.
The main disorders of cortical development include:

- Microcephaly - abnormally small head circumference
- Megalencephaly - increased brain size (assoc with learning difficulties)
- Lissencephaly - complete absence of gyri (smooth brain)
- Heterotopias - abnormal neural collections in subependymal region
- Polymicrogyria - increased number of abnormal ridges and folds (gyri)
- Disorders of cortical organisation
Malformation of the limb involve missing, incomplete, supermerary or abnormally

developed limbs that are present at birth. Most are a result of intrauterine growth inhibitions,
or disruptions to embryonic tissues, some are caused by teratogenic agents such as
thalidomide. Limb deformities can be longitudinal or transverse:
- Longitudinal
- Specific mal developments where an element of a limb is missing.
- For instance, deficiency of the radius is a common upper limb deficiency and
hypoplasia of the fibula is a common lower limb deficiency
- Most are associated with other syndromes
- Transverse
- All elements beyond a certain level are absent, and the limb resembles an
amputation stump
- Amniotic bands are a common cause, often not associated with other
symptoms.
Polydactyly is supermeruation of digits and the most frequent limb deformity. There are three
types:
- Preaxial polydactyly - extra thumb or great toe
- Central polydactyly - extra ring, middle or index finger
- Postaxial polydactyly - extra digit on the ulnar/fibular side of limb
Syndactyly is the webbing or fusion of fingers or toes, the majority are AD inherited. The
simple form is only the fusion of soft tissue while the complex form also involves the fusion of
bone.
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II. Systemic Pathology
Pathology Syllabus Notes 1

I. General Pathology 1
II. Systemic Pathology 60
Cardiovascular pathology 60
Pulmonary pathology 82
Gastrointestinal pathology 95
Hepatic and Pancreatic Pathologies 108
Renal Pathology 116
Haematologic & Bone Marrow Diseases 121
Endocrinology Pathology 135
Pathologies of the Central Nervous System 146
Pathologies of infectious diseases 152
Cardiovascular pathology
47. Atherosclerosis. Etiology, pathogenesis and general characteristics of
atherosclerotic vessel alterations.
Arteriosclerosis is the hardening of arteries, there are three types:

- Arteriolosclerosis (affects small arteries and arterioles, may be hyaline or hyperplastic
form)
- Monckeberg medial sclerosis (calcific deposits in muscular arteries
- Atherosclerosis (hardening of artery - most medically important)
Atherosclerosis
Defined by the presence of intima lesions known as atheromas (or atherosclerotic
plaques). These plaques contain a soft lipid core (mainly cholesterol with necrotic debris)
covered with fibrous plaque. These plaques obstruct the lumine, increase risk of rupture
and weaken underlying media (can cause aneurysm).
Etiology
- Non-modifiable risk factors
- Age (40-60)
- Sex (male)
- Genetics
- Modifiable risk factors
- Hyperlipidemia
- Hypertension
- Smoking
- Diabetes mellitus
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- Other factors that may play a role include stress, metabolic syndrome, and presence
of inflammatory cells in vessels
Pathogenesis
- Response to injury hypothesis
- Views atherosclerosis as chronic inflammatory process
- Endothelial injury occurs leading to endothelial dysfunction and increased
permeability
- Accumulation of lipoproteins in vessel wall
- Platelet adhesion
- Monocyte adhesion to endothelium with migration into intima and
differentiation into foam cells
- Lipid accumulation within macrophages which release cytokines
- Smooth muscle activation and proliferation
- This process causes hemodynamic disturbances within the vessel, increasing the
risk of thrombus formation (virchow's triad). Chronic dyslipidemia can impair
endothelial cell function, increasing free radical oxygen production and increasing
endothelial damage.
Pathology
- We divide the progression of atherosclerosis in different morphological states:
- Fatty streaks - begin as minute yellow molecules that coalesce into
elongated lesion. Consist of lipid-filled foamy macrophages
- Atherosclerotic plaque - here we see intimal thickening and lipid
accumulation, the plaques are white to yellow raised lesions and larger than
simple fatty streaks.
- Plaques consist of three parts 1) cells (smooth muscle, macrophages,
T-cells), 2) ECM (collagen, elastic fibers, proteoglycans), 3) lipids
48. Atherosclerosis. Types of atherosclerotic microscopic & gross

pathomorphological changes. Organ site damage in atherosclerosis.
Complications.
Atherosclerosis generally affects large and medium size arteries

(eg. aorta, carotid, coronary), the organs most likely to display
symptoms are heart (MI), brain (stroke), limbs (gangrene of
extremities) and the vessels themselves (aneurysms).
As mentioned above, the early stage of a plaque is a fatty

streak which then becomes an atheroslcerotic plaque. A
more complicated method of describing it is in the following
categories:
- Initial lesions
- Fatty streak
- intermediate lesion
- Atheroma
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- Fibroatheroma
- Complicated lesion
The outcome of the plaque depends on the size of the vessel, as well as the size and
stability of the plaque. Possible outcomes are:
- Occlusion by plaque growth
- Damage to vessel wall causing aneurysm
- Plaque rupture causing thrombus to embolize
As a plaque grows, at 70% occlusion it typically causes limits to blood supply that are
symptomatic (stable angina at 70%). There then comes a point where the plaque will have
an acute change. Symptoms due to occlusion may come before this acute change, or the
plaque may remain asymptomatic until one of the following:
- Rupture (exposing highly thrombogenic plaque elements)
- Erosion/ulceration (exposing thrombogenic subendothelial basement membrane)
- Hemorrhage into atheroma (expanding plaque volume)
49. Ischemic heart disease: myocardial infarction. Microscopic & gross

pathomorphology. Stages, complications, outcomes
Cardiomyocytes generate energy via oxidative phosphorylation, so oxygen is a must. IHD

is a term that encoupases all conditions where there is an imbalance between cardiac
perfusion and myocardial oxygen required. 90% of IHD cases are reduced coronary
blood flow due to obstructive atherosclerosis, and this is what the term generally means.
Manifestations of IHD are:
- Angina pectoris (stable, unstable, p
- Acute MI
- Chronic IHD with CHF (see below)
- Sudden cardiac death (can occur due to MI but commonly due to lethal arrhythmia)
Here we will focus on Myocardial Infarction
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- The vast majority of MIs are caused by acute coronary artery thrombosis,
generally where there is disruption of a pre existing atherosclerotic plaque that
provides thrombus generation, vascular occlusion and transmural infarction of
downstream myocardium
- 10% of MIs are due to coronary artery vasospasm or embolism for another thrombi.
- In typical MI the following events occur
- Atheromatous plaque is disrupted exposing endothelium collagen and
necrotic plaque
- Platelets adhere, aggregate and are activated
- Activation causes coagulation and the thrombus is generated
- Myocardial response to MI
- Loss of ATP production has rapid functional effect with ultrastructural
changes (including myofibrillar relaxation and mitochondrial swelling). These
early stages are reversible
- Ischemia after 20-40 minutes is irreversible and leads to coagulative
necrosis
- MIs also commonly trigger arrhythmias (e.g. ventricular fibrillation)
- We can describe infarcts as transmural or non-transmural. Transmural means
that the necrosis spreads through the whole thickness of the myocardium,
non-transmural does not.
Myocardial infarcts less than 12 hours old are not grossly apparent, however, less than 3
hours old can be visualised by staining. 12-24 hours after the event, a red-blue
discolouration should be visible caused by stagnated blood, over the following weeks, a
fibrous scar will evolve.
Stages
- Time - gross examination - histopathology
- <30 mins - None - None
- 30 mins - 4 hours - none - glycogen depletion (PAS stain) + waviness of fibers
- 4-12 hours - sometimes dark mottling - coagulative necrosis, edema, hemorrhage
- 12-24 hours - dark mottling - karyopyknosis, hypereosinophillia, neutrophil infiltration
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- 1-3 days - infarct center yellowish - continued coag necrosis, loss of nuclei, increased
neutrophil infiltration
- 3-7 days - hyperemia at border, softening yellow center - beginnings of disintegration
of dead myocytes, macrophage removal at border
- 7-10 days - maximally soft with red margins - increased phagocytosis and granulation
- 10-14 days - red-gray - mature granulation with type I collagen
- 2-8 weeks - gray-white granulation tissue - decreased cellularity, increased collagen
Complications/Outcomes
- Contractile dysfunction - severe pump failure that can cause cardiogenic shock (aka
Acute heart failure)
- Papillary muscle dysfunction - causing post infarct mitral regurgitation
- Myocardial rupture - up to 3% of cases, is fatal
- Arrhythmias
- Pericarditis
- Chamber dilation - due to necrotic weakening of muscle
50. Chronic ischemic heart disease: pathogenesis, microscopic & gross

pathomorphology; systemic and organ-specific manifestations
Chronic IHD is a form of progressive heart failure due to ischemic myocardial damage,
often with the background of previous MI. Chronic IHD occurs when compensatory
mechanisms (e.g. hypertrophy) for the MI fail.
Typically patients display left ventricular dilation with hypertrophy, with moderate to
severe atherosclerosis of the coronary arteries. Histopathologically, we see fibrosis and
subendocardial myocyte vacuolization due to previous MI. The gross pathology we
would expect to show previous MI scars on the myocardium.
For pathogenesis really look at acute IHD and Atherosclerosis, as this is simply the chronic
form of this!
I don’t really know what is wanted beyond the blindingly obvious here, it’s HF (remember the
symptoms), its chronic, it’s due to ischemic changes (see above pathohistology)....yeh….
51. Systemic arterial hypertension: vascular and organ-specific

pathomorphological changes
Blood pressure is determined by Cardiac Output x Peripheral Resistance (image).
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Hypertension is when blood pressure is high (>140/90). Hypertension causes increased risk
of:
- Cardiac hypertrophy and heart failure
- Aortic dissection
- Multi-infarct dementia
- Renal failure
- Atherosclerosis
- Stroke
Hypertension is generally considered an issue of both genetic and environmental origins,

which increase blood volume and/or peripheral resistance. Hypertension can be primary
(essential), 95% of cases, or secondary (due to a renal, endocrine, cardiovascular or
neurological disorder).
Not only does hypertension increase atherosclerosis, but it also causes arterial wall
changes, which can cause aortic dissection and cerebrovascular hemorrhage.
In small vessels (i.e. in the organs), there are two key changes we should be aware of:
- Hyalinization
- Hyperplastic arteriosclerosis
Hyaline atherosclerosis is the deposition of hyaline into the small vessels and loss of
underlying wall structure with luminal narrowing. One organ is this is most notable is the
kidneys, where nephrosclerosis can occur with diffuse vascular compromise.
Hyperplastic arteriosclerosis causes laminated thickening of the arteriolar wall due to

smooth muscle cell hypertrophy and reduplication of the basement membrane (looks
like an onion skin), in malignant hypertension these changes are accompanied by fibrinoid
deposits and wall necrosis (necrotizing arteriolitis). This is again most common in the
kidney.
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Hypertensive heart disease is a slightly separate topic and worth touching on. Mostly note
that it requires two conditions to be met for diagnosis:
- Left ventricular hypertrophy in absence of other cardiovascular pathology
- And history of hypertension
52. Pulmonary hypertension. Etiology, types. Cor pulmonale. Right ventricle and
pulmonary vessel microscopic & gross pathomorphology
Cor pulmonale is shorthand for pulmonary hypertensive heart. It consists of right

ventricular hypertrophy and dilation, often accompanied with right heart failure. It is
exclusively caused by pulmonary hypertension.
Pulmonary hypertension is defined as pulmonary arterial pressure exceeding 25 mm Hg at

rest or 30 mmHg in exercise. This increased pressure means the right side of the heart has
to work harder, causing hypertrophy, and there is a build up of blood in the R side of the
heart, causing dilation. It is caused by a number of conditions that affect the lung or the left
side of the heart, etiological causes include:
- WHO group I - pulmonary arterial hypertension
- Idiopathic
- Heritable
- Drug toxicity
- CT disease, HIV infection, portal hypertension, congenital disorders
- WHO group I’ - pulmonary veno-occlusive disease, pulmonary capillary
hemangiomatosis
- WHO group I’’ - persistent pulmonary hypertension of the newborn
- WHO group II - pulmonary hypertension secondary to left heart disease
- L systolic/diastolic dysfunction
- Valvular heart disease
- Congenital disease
- WHO group III - pulmonary hypertension due to lung disease
- COPD
- Interstitial lung disease
- Sleep apnea
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- Bronchiectasis
- WHO group IV - chronic arterial obstruction
- Chronic thromboembolic pulmonary hypertension
The pathogenesis should be clear. In Lung disease causes we have increased resistance, in
heart causes we have increased amounts of blood, we know these cause hypertension.
Pathology of vessels/lungs
- Features characteristic of pulmonary hypertensive vascular remodeling include:
- Increased vascular stiffening of proximal pulmonary arteries
- intima/medial thickening of arteries
- Development of vaso-occlusive lesions
- Increased smooth muscle proliferation
In the below image we can see arteries in pulmonary hypertension with thickened walls.
- When we consider the gross morphology, we should take particular note of the lungs
which become heavy, fluid filled, and sometimes frothy, due to the congestion of
blood that occurs in cases of pulmonary hypertension.
Right ventricular pathology

- The key change here is the hypertrophy of the myocardium of the right ventricle, as is
visible on the image below, along with right ventricular dilation.
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53. Endocarditis: classification, etiology, pathogenesis, pathomorphology.

Infective endocarditis - acute and subacute forms
This is the inflammation of the inner layers of the heart, the endocardium, and commonly
affects the heart valves, interventricular septum and chordae tendineae. It is
characterised by lesions, known as vegetations, formed of masses of platelets, fibrin and
microorganisms.
Endocarditis can be infective or non-infective. Alternatively, it can be chronic or acute

(which further divides into acute and subacute), or Left or Right. Risk factors for all forms
include Pacemakers, artificial valves and other disruptions to the physiological endothelium.
- Infective endocarditis
- Caused by microbes, most commonly Strep, followed by Staph.
- Symptoms include fever, small areas of bleeding into the skin and tiredness.
Complications may include valvular insufficiency (regurgitation), heart failure,
stroke, sepsis and kidney failure
- Classic diagnostic triad: persistent fever, emboli, new/changing
murmurs
- Risk factors include artificial valves, hemodialysis and pacemakers
- The most common bacteria are streptococci or staphylococci
- Non-infective endocarditis
- Also known as nonbacterial thrombotic endocarditis, usually occurs in
hypercoagulability state - commonly system-wide bacterial infection,
pregnancy or venous catheters.
An additional note about Right sided endocarditis, this is most common in IV drug users
and patients who have pacemakers.
Endocarditis typically develops friable vegetations composed of necrotic debris,

thrombus and organisms, commonly found in aorta, aneurysmal sacs and around the
valves (aortic and mitral most common targets). These vegetations may be single or
multiple, and can erose the underlying myocardium to produce an abscess cavity (ring
abscess). Shedding of the vegetations is common due to their friability, it is this which
leads to development of sub dermal septic infarcts and mycotic aneurysms.
Acute form
- Refers to destructive and highly virulent forms, attacking a previously normal valve
and capable of causing rapid death
Subacute form
- Low virulence organism, involving a previously abnormal heart (e.g. artificial valves).
- Can be insidious and even untreated for a long time
Investigations for both types include blood cultures, echocardiography, urine analysis (to
observe haematuria) and blood tests to observe changes in RBCs count (anemia),
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leukocytosis, and check LFTs (may show increased serum alkaline phosphatase). Chest
radiology may reveal heart failure or emboli, while ECG may show MI due to emboli.
54. Valvular heart disease: classification, microscopic and gross pathomorphology
The valvular disorders we shall consider:

- Mitral stenosis
- Mitral regurgitation
- Aortic stenosis
- Aortic regurgitation
Before we get stuck in, I want to nail down rheumatic fever, because it is a topic that keeps
appearing but I have a very vague understanding of it. Rheumatic fever is the result of an
untreated infection of Streptococcus pyogenes in the throat. 3% of untreated patients
produce antibodies against the microbe that damage the CT around arterioles. It is in
effect a type II hypersensitivity reaction. The CT most commonly affected is the joints
(ence Rheumatic) and the heart, specifically, the heart muscle protein myosin.
RF can then go on to cause changes of valves in the heart, including valve thickening,
fusion and changes to the tendinous cords. Fibrosis and scarring of the valve leaflets is
visible. On autopsy, the classic triad of findings of RH in the heart are:
- Mitral valve thickening
- Thickened chordae tendineae
- Left ventricular hypertrophy (compensation for mitral dysfunction)
Microscopically, we can also observe Aschoff bodies in acute rheumatic carditis. These are
myocardial inflammatory lesions, collections of lymphocytes, scattered plasma cells
and activated macrophages known as anitschkow cells. These bodies can be found in
any of the layers of the heart, hence why rheumatic fever can be thought to cause
pancarditis.
We can diagnose RF with evidence of two of the following, in combination with Elevated
antistreptolysin O titre:
- Polyarthritis
- Carditis
- Subcutaneous nodules (collagen fiber collections over bones or tendons)
- Erythema marginatum (rash on trunk or arms as macules)
- Sydenham’s chorea (a series of involuntary rapid movements of face and arms)
Prevention, with early treatment of strep throat, is most important step, but treatment can be
with anti-inflammatories (e.g. aspirin/corticosteroids) and ABs if strep still present.
OK, now some valvular disorders.
Mitral stenosis
The mitral valve separates the Left Atrium from the Left Ventricle. It consists of an
Anterior and Posterior leaflet.
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During diastole, the mitral valve opens and allows blood from the left atria into the left
ventricle, if the valve doesn not open enough, this is known as mitral valve stenosis.
Mitral valve stenosis is when the valve area drops to 2cm2 compared to the normal
4-6cm2. It leads to a ‘snap’ sound following S2, along with a diastolic rumble, as a result
of abnormal blood flow as the blood tries to get from the left atria to the ventricle.
Etiology
- Caused by congenital heart defects or rheumatic heart disease
Signs/Symptoms
The primary symptom is pulmonary congestion and edema, leading to dyspnea. This is
as a result of build up of blood in the left atria, triggering increased pulmonary pressure.
This increased pulmonary pressure in turn makes it harder work for the right side of the
heart, and can cause right sided heart failure.
Mitral Stenosis also causes atrial dilation, due to the increased volume of blood, this
increases risk of Atrial fibrillation, which in turn increases the risk of Thrombus
formation. An important symptom is the possible compression of the oesophagus,
making swallowing hard.
Mitral valve regurgitation

Etiology
- Most common cause is mitral valve prolapse
- The papillary muscles and chordae tendineae are responsible for holding
the mitral valve in place while closed. When these are weakened we get
mitral valve prolapse. The weakening of these muscle and tendons is
known as Myxomatous Degeneration.
- The cause for this is not well known, however genetic diseases like
Marfan's and Ehlers-Danlos can trigger it.
- Damage to heart by heart attack
- Left sided heart failure leading to left ventricular dilation
- Rheumatic fever (leading to chronic rheumatic heart disease)
Symptoms
- A mid systolic click, a result of the ‘flapping’ of the mitral valve leaflets, and
systolic murmur, caused by the abnormal movement of blood from the left ventricle
back into the left atria during systole, are audible.
- Left ventricle undergoes eccentric hypertrophy to compensate for the volume
overload caused by incomplete evacuation of blood from the heart during systole
- Can lead to angina pectoris and eventually left sided heart failure
- In chronic form we start to see lung congestion and lung edema. This is because the
increased left atrial pressure prevents venous return from the lungs, increasing
pulmonary circulatory pressure.
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- Lung edema leads to dyspnea and orthopnea

- We also witness a decreased minute volume (total blood supplied to the systemic
circulation) as part of the blood is being pumped back into the left atria instead of the
aorta.
Aortic Stenosis
The Aortic valve goes from the Left Ventricle to the Aorta. It is made up of three leaflets,
the Left, Right and Posterior.
It opens during systole to allow for blood to move to the body, it closes during diastole to
allow the ventricle to fill.
When the valve fails to open all the way during systole, this is known as Stenosis. Stenosis
is defined as being when the valve has an open area of less than 1cm2, compared to the
normal 3-4cm2. It is noticeable through auscultation by listening for the
crescendo-decrescendo murmur between S1 and S2.
Etiology
- Stress over time - appears in late adulthood and we see calcification and fibrosis of
valve. Always develops chronically
- Congenital defect - e.g. being born with a bicuspid aortic valve instead of tricuspid
- Chronic rheumatic fever - causes fibrosis which fuses the leaflets together
Symptoms
- Triggers concentric left ventricular hypertrophy as a result of increased afterload
- This causes angina pectoris
- Reduced Cardiac Output can lead to syncope with eventual congestive heart failure
- Occasionally, Microangiopathic hemolytic anemia can occur, which is when the RBCs
are broken into fragments when passing through the stenotic valve. This causes
haematuria along with anemic symptoms.
Treatment
- Valve replacement
Aortic regurgitation
The aortic valve closes during diastole to allow the ventricle to fill, if the valve does not
successfully close and remains open, this is known as aortic regurgitation (/insufficiency)
and blood moves back into the ventricle from the aorta.
This movement of the blood back into the aorta is heard in the form of a Decrescendo
Diastolic Murmur (S2 sounds drawn out and ‘decrescendo-ing).
Etiology
- 50% of cases due to aortic root dilation, where the start of the aorta widens
- 80% of these are idiopathic, 20% due to aortic dissection, aneurysms and
syphilis
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- The other 50% are due to valvular damage causing fibrosis, possible causes include
- Infective endocarditis
- Chronic rheumatic fever
Symptoms
- Blood flowing back into the left ventricle increases the blood volume, increasing the
stroke volume and cardiac output. This causes eccentric hypertrophy of the left
ventricular myocardium, expanding the size of the heart
- This expansion will move the apex of the heart laterally
- Systolic blood pressure will increase, due to the increased cardiac output, while
diastolic blood pressure will decrease, due to black flow from the aorta. This widened
blood pressure gap is typical for Aortic Insufficiency (known as hyperdynamic
circulation).
Treatment
- Valve replacement
There are a number of notable signs of aortic regurgitation, these are:

- Water-hammer pulse
- De Musset sign - bobbing head
- Hill sign - popliteal cuff pressure 40 mmHg higher than brachial cuff pressure
- Duroziez sign - systolic murmur over femoral artery with compression of artery,
diastolic murmur with femoral artery dilation
Valve Auscultation Cardinal symptoms

disorder
Mitral stenosis Post S2 snap with diastolic low Causes pulmonary congestion and atrial dilation
rumble (increased AF and R HF failure risk)
Mitral Mid systolic click with systolic Causes L ventricular eccentric hypertrophy, can lead
regurgitation murmur to lung congestion and edema due to increased L
ventricular and then L atrial pressure
Aortic stenosis Systolic crescendo-decrescendo Reduced ejection fraction and left ventricular dilation
murmur with associated symptoms
Aortic Diastolic decrescendo murmur Eccentric hypertrophy of L ventricle, increase in

regurgitation (S2 drawn out) systolic BP, decrease in diastolic BP (water hammer
pulse)
55. Myocarditis: classification, pathomorphology
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Also known as inflammatory cardiomyopathy, it is inflammation of the heart muscle.

Symptoms include shortness of breath, chest pain (stabbing in nature), decreased exercise
tolerance, and arrhythmias. In infectious causes fever is also common.
Etiology and Classification

Most commonly caused by viral infections (adenovirus, parvovirus, coxsackie virus,
rubella, Epstein-Barr, HIV), but other causes include bacteria (Brucella, corynebacterium
diphtheria, haemophilus influenzae), protozoan (Trypanosoma cruzi) and Fungal
(Aspergillus). Non infectious causes include drugs (alcohol, clozapine), and autoantigens.
These two etiologies, give it it’s classification, infectious and non-infectious.

Non-infectious myocarditis can be further broken down to hypersensitivity myocarditis,
Chagas myocarditis and Giant cell myocarditis.
Pathomorphology
The mechanism sees the infiltration of the heart tissue by pro-inflammatory blood cells,
causing an inflammatory response in the myocardium. Morphologically the heart may appear
normal or dilated in the acute stages, in advanced stages the myocardium appears flabby
and mottled with pale and hemorrhagic areas.
Microscopically, the myocarditis can be seen to be edematous, with inflammatory cell

infiltrates. After resolution, if the patient survives, the myocardium can survive without
significant dysfunction.
In non-infectious cases of myocarditis, the cellular infiltrates are dominated by lymphocytes,

macrophages and a high proportion of eosinophils (giant cell myocarditis unsurprisingly
has a high number of giant cells…).
Diagnosis and Treatment

Diagnosis is based on ECG and/or C-reactive protein and/or erythrocyte sedimentation rate
and/or biopsy and/or MRI showing decreased uptake of contrast due to scars. Makers of
myocardial damage are also elevated (troponin, CK). Basically, looking for evidence of
inflammation AND myocardial damage.
Treatment is supportive in viral form. Digoxin and diuretics may help in acute stage (reduce
heart work), ACE inhibitors may also be used. Systemic corticosteroids may or may not be
beneficial. Where drugs do not work, surgery is indicated.
56. Pericarditis: etiology. Pathomorphological types
This is the inflammation of the pericardium, the fibrous sac that surrounds the heart.
Typically sudden onset of sharp chest pain that is relieved by sitting up. Pain often
radiates to shoulders, neck or back. Other symptoms include fever, weakness, palpitation
and dyspnea.
Etiology
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Common etiology is bacterial or viral (In the developed world, 85% of cases are caused by
viruses, while in the developing world Mycobacterium tuberculosis (TB) is a more common
etiological factor). Viral causes include coxsackievirus, herpesvirus and mumps.
Non-infective etiology includes AI (lupus is common cause), MI, Trauma, uremia, cancer,
side effect of drug (e.g. isoniazid, cyclosporine, warfarin, heparin) and aortic dissection.
Pathomorphological types
The pathomorphology of the condition varies based on the etiology:
- In patients with acute viral pericarditis or uremia, exudate is fibrinous, with irregular
shaggy pericardial appearance
- In acute bacterial pericarditis the exudate is fibrinopurulent, with ‘frank pus’ areas
- Pericarditis due to malignancy is often associated with shaggy fibrinous exudate and
bloody effusion
Pericarditis can resolve without problems, or result in chronic pericarditis, associated with
adhesions and fibrotic scars in the pericardial space. This can in turn result in constrictive
pericarditis.
Diagnosis and treatment

Diagnosis can be based on increased urea (BUN), or increased creatinine, but best
diagnosis is with ECG, showing saddle shaped ST elevation in all leads except aVR and
V1! Note, this is different from MI elevation as the elevation comes out of the S wave,
in MI, the elevation comes straight out of the R wave.
On physical examination, there is often evidence of a pericardial friction rub, with a

diastolic knock. Complications include pericardial effusion and cardiac tamponade.
Treatment of viral or idiopathic form is with aspirin or NSAIDs,

Colchicine can also be added to limit future cases of pericarditis. In
bacterial cases, ABs should be given IV. Pericardiocentesis can also
be performed to treat pericardial effusion/tamponade.
57. Cardiomyopathies: classification, pathomorphology
Cardiomyopathies are cardiac muscle diseases, commonly

secondary to other conditions (e.g. coronary atherosclerosis,
hypertension or valvular heart disease). Diseases under the
umbrella of cardiomyopathies include:
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- Myocarditis
- Immunological diseases such as sarcoidosis
- Systemic metabolic disorders such as hemochromatosis
- Muscular dystrophies
- And genetic disorders
Common pathomorphological classification is as follows:

- Dilated cardiomyopathy
- Hypertrophic cardiomyopathy
- Restrictive cardiomyopathy
Dilated cardiomyopathy
- Progressive cardiac dilation and contractile dysfunction with concurrent hypertrophy
- Morphologically, the heart is obviously enlarged, with flabby distention of all
chambers.
- Ventricular thickness may be less than, equal to or greater than normal, depending
on the extent of hypertrophy compared to distension
- Possible causes include
- Genetic
- Infections
- Toxic exposure
- Iron overload
- In these cases, hemosiderin is visible with Prussian blue staining
- Histologically, most myocytes exhibit hypertrophy with enlarged nuclei, as well as
being stretched and irregular
- Symptom are really that of progressive CHF, with dyspnea, fatigue and poor exercise
tolerance. We fundamentally see loss of myocardial contraction (reduced EF).
Hypertrophic Cardiomyopathy
- Myocardial hypertrophy with defective diastolic filling (and in ⅓ of cases, outflow
obstruction)
- Effectively, the myocardium thickens, heart is thick-walled and heavy with
hypercontractility (think the opposite to DCM). Failure of the myocardium to
effectively relax means deficient diastolic filling.
- Most common cause is genetic, a disorder of sarcomeric proteins (most commonly
beta myosin).
- Morphologically, we have massive myocardial hypertrophy without dilation. On
longitudinal section the very narrow left atria is visible (see below).
- Histologically, look at hypertrophy and haphazard myocyte organisation
- Symptoms are in line with expected, decreased preload means decreased CO, along
with hypertrophy increased Ischemic risk (increased myocytes = increased demand),
which can cause MI.
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Restrictive cardiomyopathy
- A primary decrease in ventricular compliance resulting in impaired ventricular filling
during diastole
- Ventricles are of normal size, but there is no compliance so ventricles cannot fill.
Microscopic examination shows interstitial fibrosis
- Etiology is generally idiopathic or as a result of a systemic disease (e.g. radiation
fibrosis, amyloidosis, sarcoidosis or genetic metabolic deficiencies)
- Specific forms mentioned
- Amyloidosis - occurs with systemic amyloidosis, particularly in senile cases
- Endomyocardial fibrosis - commonly in young people in Africa and tropical
regions. Fibrosis is found in the endometrium specifically.
- Loeffler endomyocarditis - also with endocardial fibrosis, typically with large
mural thrombi but no geographic predisposition.
58. Vasculitis: classification, pathomorphology, Types of aneurysms
Vasculitis is vessel wall inflammation, it can affect small or large vessels, different types of
vasculitis have different preferences (there are 20 different primary forms of vasculitis). We
generally divide vasculitis into arteritis and phlebitis.
Classifications can be as follows:

- Based on etiology
- Infectious
- Autoimmune/immune mediated
- Based on location of affected vessels
- Vasculitis limited to skin
- Necrotizing vasculopathies
- Musculoskeletal vasculitis
- Type blood vessels
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- Arteritis
- Phlebitis
- Size of blood vessel
- Large (e.g. Takayasu’s arteritis, Temporal arteritis)
- Medium (e.g. polyarteritis nodosa)
- Small (e.g. eosinophilic granulomatosis with polyangiitis)
Many patients with vasculitis have circulating Anti-neutrophil cytoplasmic antibodies,

which are directed at enzymes of neutrophil primary granules, monocytes lysosomes
and endothelial cells. They are a useful diagnostic marker for immune-associated vasculitis
as well as having a close relationship with the severity of the vasculitis.
Here we will evaluate some of the most common vasculitis types:

- Giant cell (temporal) arteritis
- Most common form of vasculitis in elderly in developed countries
- Is a chronic, granulomatous inflammation of large/small arteries, especially
temporal arteries
- Can cause blindness if not treated
- PG sess T-cell mediated immune response to vessel wall inflammation
causing granulomatous inflammation
- Artery exhibits patchy nodular intima thickening and occasional thromboses,
with lumen narrowing and classic granulomatous inflammation and
fragmentation of the internal elastic lamina.
- Clinical signs include fever, fatigue, facial pain/headache that is most severe
on superficial temporal side, and most importantly, painful palpation of the
temporal artery
- Takayasu arteritis
- Granulomatous vasculitis of medium and larger arteries characterised by
ocular disturbances and weakened brachial pulse.
- Mainly causes transmural scarring and thickening of aorta (arch and great
vessels most commonly affected).
- Inflammation is associated with intimal hyperplasia, adventitial fibrosis and
irregular patches of thickening.
- Polyarteritis nodosa
- Systemic vasculitis of small arteries, particularly renal and visceral vessels
- It causes a form of necrotizing inflammation often with thrombosis. Kidney,
heart liver and GI tract are all affected, lesions generally affect only part of the
vessels circumference. Causes weakening of the vessels increasing risk of
ulcerations, infarcts, ischemic atrophy and hemorrhages.
- It is predominantly a disease of young people, clinical course is generally
chronic with acute episodes. Classic presentation can see a combination of
rapidly increasing hypertension, bloody stools and diffuse muscular pains and
neuropathies.
- Other important types include Kawasaki disease, Microscopic Polyangiitis,
Wegener granulomatosis, Churg-Strauss syndrome and Thromboangiitis
Obliterans
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Types of Aneurysm
- Congenital or acquired dilations of blood vessels or the heart
- True aneurysms involve all three layers of the artery (intima, media and adventitia),
false aneurysms do not involve all three layers, instead a wall defect causes an
extravascular hematoma that communicates with the intravascular space
- Note, this is different from a dissection where there is not the same
communication
- Pathogenesis: aneurysms occur when the structure or function of CT is compromised
by:
- Inadequate or abnormal CT synthesis
- Excessive CT degradation
- Loss of smooth muscle cells
- Atherosclerosis and hypertension are huge risk factors.
59. Systemic connective tissue disease. Lupus

erythematosus. Polyarteritis nodosa.
Right, learn this, because I don’t know it. Lupus is an

autoimmune disease. Commonly, anti-nuclear antibodies
are produced which target the body's own cells, it is
fundamentally a failure in the bodies ability to maintain
self-tolerance.
Etiology is a number of factors:

- Partly genetic
- HLA (Human leukocyte antigen gene complex)
genotype
- Environmental factors
- UV, Smoking, Sex hormones (2x/3x more
common in women), Drugs
- Immunological abnormalities
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The proposed pathogenic model is that UV irradiation and other environmental insults
lead to apoptosis of cells, with inadequate clearance of the nuclei of these cells, there is
a large number of nuclear antigens. Various genetic abnormalities then lead to
defective ability to maintain self tolerance in B and T lymphocytes. These self reactive
cells then cause systematic cellular damage.
This tissue damage is mediated in a number of ways:

- Most organ damage is due to immune complex deposition
- Antibodies of different specificities can contribute to the pathology of SLE.
Autoantibodies against RBC and WBC and platelets cause cytopenias, while
autoantibodies against phospholipids increased risk of thrombosis
The impact of lupus is diverse:

- Blood vessels
- Causes acute necrotizing vasculitis
- Kidneys
- Causes all forms of glomerulonephritis
- Skin
- Causes photosensitivity and the butterfly rash across the face
- Joints
- Diffuse joint pain and swelling
- CNS
- Vascular lesions can cause focal or diffuse neurologic defects
- Other organs
- Onion-skin lesions on the spleen
- Pericardium and pleura may undergo inflammatory changes
- We may observe Libman-Sacks endocarditis in the heart
Polyarteritis nodosa
- Systemic vasculitis of small arteries, particularly renal and visceral vessels
- ⅓ of patients have Hep B which leads to formation of immune complexes
containing Hep B antigen which is deposited in the vessels. In the remaining ⅔
the cause is unknown.
- It causes a form of necrotizing inflammation often with thrombosis. Kidney,
heart liver and GI tract are all affected, lesions generally affect only part of the
vessels circumference. Causes weakening of the vessels increasing risk of
ulcerations, infarcts, ischemic atrophy and hemorrhages.
- It is predominantly a disease of young people, clinical course is generally chronic
with acute episodes. Classic presentation can see a combination of rapidly
increasing hypertension, bloody stools and diffuse muscular pains and
neuropathies.
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60. Systemic connective tissue disease - rheumatoid arthritis, dermatomyositis,

systemic sclerosis (scleroderma).
Rheumatoid arteritis
- Autoimmune disease that affects joints causing
them to become warm, swollen and painful, often
worse following rest
- Most commonly wrist and hands are involved. Can
also cause anemia, pericarditis and tiredness
- Cause is a combination of genetic and
environmental factors, underlying mechanism is
cytokine-mediated inflammation with CD4 T
cells being the source, with production of
antibodies against cyclic citrullinated peptides
which cause lesions on the joints. A ntibodies
are further directed against citrullinated
fibrinogen, type II collagen, alpha-enolase and
vimentin.
- On histology, chronic papillary synovitis is visible
with dense perivascular inflammatory cell
infiltrates and increased vascularity along with
neutrophil aggregates and increased osteoclast
activity
Dermatomyositis
- Is the most common inflammatory myopathy in children, although it can occur in
adults where it is a paraneoplastic disorder. In both cases it is autoimmune.
- It is an example of a primary inflammatory myopathy.
- The disease sees perivascular mononuclear cell infiltrates with tubuloreticular
inclusions in endothelial cells and myofiber damage .
- Type 1 interferon-induced gene produces are upregulated in affected muscles.
- It causes skin rash, muscle weakness and inflammatory myopathy
Scleroderma
- A systemic immunological disorder characterised by excessive fibrosis in multiple
tissues, obliterative vascular disease and evidence of autoimmunity.
- Scleroderma is somewhat of a misnomer as while the skin is it’s main target, lesion
are present throughout the body.
- Two groups:
- Diffuse scleroderma - early widespread skin involvement and rapid
progression
- Limited scleroderma - generally confined to skin of face and fingers,
involvement of rest of the body occurs later
- Pathogenesis is uncertain, but thought to go like this:
- Injury to endothelial cells by unknown mechanisms causes T-cell migration
and activation
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- T-cells respond to some self antigen, which activate macrophages

- Macrophages and T-cells release cytokines that stimulate fibroblasts
- B-Cell activation also occurs, directed against DNA topoisomerase I
- Morphologic changes - can affect any organ:
- Skin
- Diffuse, sclerotic atrophy of skin, usually beginning in fingers before
moving to arms, shoulders, neck and face.
- Histopathology shows edema and perivascular infiltrate with CD4+
T-cells.
- Capillaries are thickened, with endothelial damage and partial
occlusion.
- GI tract
- Affected in 90% of cases
- Progressive atrophy and collagenous fiber replacement throughout GI
tract (most severe in esophagus)
- Degenerative changes lead to loss of villi and microvilli, causing
malabsorption, increased risk of ulceration and rupture.
- Musculoskeletal system
- Synovial hyperplasia and inflammation early on followed by fibrosis
- Similar changes to Rheumatoid Arteritis
- Kidneys
- Renal abnormalities in ⅓ of patients
- Associated with thickening of vessel walls of interlobular arteries with
intimal cell proliferation and deposition glycoproteins and
mucopolysaccharides
- Heart
- Patchy myocardial fibrosis occurs
Affects women more than men, presentation of SS, RA, SLE and dermatomyositis all have
large crossovers.
Pulmonary pathology
61. Bronchitis - acute and chronic. Bronchiolitis. Pathomorphology
Acute bronchitis
Also known as a chest cold, this is the i nflammation of the bronchi of the lungs.
Common symptoms include cough, mucus, wheezing & fever. The cough may persist for a
number of weeks after the initial infection, itself lasting about a week. It is notable that the
cough often occurs on expiration. Bronchitis caused by adenoviridae may also cause GI
symptoms.
More than 90% of cases are viral (rhinovirus, influenza etc), with RF including smoke, dust
and air pollution. Bacterial cases are due to Mycoplasma pneumoniae or Bordetella
pertussis.
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Damage caused by irritation of the airways leads to inflammation and neutrophils

infiltrating tissue, this causes mucosal hypersecretion from goblet cells which can cause
obstructive symptoms.
Diagnosis is generally clinical, chest X-ray can rule out pneumonia, sputum sample shows
neutrophil granulocytes and a pathogenic microorganism. Treatment is generally not
required, the condition is self limiting.
GP NOTEBOOK SAYS:
There is some evidence that ABs have a slight beneficial benefit in treatment of
uncomplicated care, but it is minimal. Guidelines suggest not ABs if no comorbidity,
consider 7 day delayed AB with advice, noting that symptom resolution can take 3 weeks
or more!
If patient requires ABs, a five-day course of amoxicillin (500mg three times a day).
Chronic bronchitis
Most common among smokers and those in highly polluted cities. Diagnosis based on
clinical grounds; presence of persistent productive cough for at least 3 months in at
least 2 consecutive years.
The key pathogenic feature of chronic bronchitis is hypersecretion of mucus in the

bronchi caused by hypertrophy of the submucosal glands in the trachea and bronchi,
and goblet cell metaplasia. This is due to chronic irritation of the airways by inhaled
substances. The mucous plugging that then occurs in the bronchial lumen help to provide a
place for bacteria and viruses to take root and cause an inflammatory response. Irritation of
the bronchi causes infiltration of CD8+ lymphocytes, macrophages and neutrophils into
the mucosa, this is in contrast to asthma (a diff dx) where this does not occur.
Chronic bronchitis often occurs with emphysema (see 67, 68), and combine to cause
Chronic Obstructive Pulmonary Disease (COPD).
Clinical manifestation is that of a prominent cough with or without persistent sputum

production. Most significantly however, chronic bronchitis can go on to cause COPD with
outflow obstruction, causing hypercapnia, hypoxemia, and cyanosis (blue bloaters).
GP NOTEBOOK SAYS
The aim of treatment is to improve long term lung function, and improve overall quality of
life. To do this, a management plant should assess and monitor disease, reduce risk
factors, manage stable COPD and manage exacerbations (acute bouts of bronchitis).
Treatment can be:

- Pharmacological
- Bronchodilators (beta2 agonists (long and short acting), antimuscarinics,
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methylxanthines, combination therapy, anti-inflammatory therapy, long term

erythromycin to reduce exacerbations
- NICE suggests inhaled corticosteroids where FEV1 < 50%
- Non-pharmacological
- Reduction of risk factors
- Vaccines
- Oxygen therapy
- Pulmonary rehabilitation
Bronchiolitis
While bronchitis is the inflammation of the bronchi, bronchiolitis is inflammation of the
bronchioles. It is the most common respiratory tract disease in the first year of life, and
generally presents with increased work of breathing. It is important not to mistake for
common cold, listen for wheeze and/or crackles on auscultation. Symptoms are generally
mild, and only last a short period of time. It is a common condition, 1 in 3 develop the
condition, with 2-3% requiring hospitalization.
90% are caused by respiratory syncytial virus, the others due to parainfluenza virus,
influenza virus, rhinovirus and adenoviruses. Breast feeding is good for prevention, smoking
is a RF.
62. Bronchiectasis - congenital and acquired. Bronchiectatic disease.

Complications
Bronchiectasis is the permanent dilation of bronchi and bronchioles caused by

destruction of muscle and elastic tissue due to chronic necrotising infections. It can
really be considered a complication to persistent infections or obstructions. It usually affects
the lower lobes bilaterally, although when caused by a tumour or aspiration of an FB may
affect a single lobe. Airways may be dilated up to 4x, and gross examination shows huge
holes.
Common causes are:

- Bronchial obstruction (due to tumors, FBs or impaction of mucus)
- Bronchiectasis is localised to obstructive lung segment
- Congenital conditions (e.g. cystic fibrosis, immunodeficiency states, kartagener
syndrome)
- Due to the excess mucous (CF), constant infections (ID states) or structural
abnormality of mucociliary transport system (Kartagener syndrome)
- Necrotising, or suppurative pneumonia (particularly with virulent organisms such as
S. aureus or Klebsiella spp.)
All of these have the same PG. Blockage/chronic infection leads to inflammatory damage of
bronchial wall, with accumulation of exudate and further distended airways, causing
irreversible distension.
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Clinical manifestation is that of severe, persistent cough with mucopurulent sputum

which may contain blood. Symptoms are often episodic, and brought on by upper
respiratory tract infections. In the most severe cases, hypoxemia, hypercapnia, pulmonary
hypertension and cor pulmonale can then commence. Less frequent complications
include metastatic brain abscesses and reactive amyloidosis.
GP NOTEBOOK SAYS
Treatment:
- Physiotherapy which includes airway clearance techniques and exercise (e.g
postural drainage)
- Simple airway clearance techniques like active cycle of breathing and positive
expiratory devices in non-cystic fibrosis cases
- Nebulisation of normal saline or beta 2 agonists
- Inhaled steroids and AB in infective cases
- Surgical lung resection may also be considered
63. Lobar (croupous) pneumonia. Stages of development. Complications.
Pneumonia can be classified as lobar (croupous) pneumonia, lobular (broncho)

pneumonia or interstitial pneumonia. These classifications are based on the anatomical
location of the infection. Bronchopneumonia is patchy, and generally involves more
than one lobe, while lobar pneumonia affects a single lobe. More commonly however
these days, we distinguish pneumonia based on community-acquired or hospital
acquired forms.
All pneumonias can be described as an inflammatory condition affecting the alveoli,

where exudative fluid fills the alveolar spaces. Symptoms can include productive or dry
cough, chest pain, fever, and difficulty breathing. Chest X-ray, blood tests and sputum
cultures are the best way of diagnosing patients.
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Streptococcus pneumoniae is responsible for more than 90% of lobar pneumonias.
Bronchopneumonia occurs more commonly at extremes of age, while lobar pneumonia can
occur at any age.
Lobar pneumonia goes through four stages:

- Congestion
- Affected lobe(s) are heavy, red and bogy with vascular congestion, scattered
neutrophils and many bacteria in alveoli
- Red hepatization
- The lung starts to display a liver like consistency, as alveolar spaces are filled
with neutrophils, RBCs and fibrin
- Gray hepatization
- The lung becomes dry, gray and firm as the RBCs are lysed while
fibrinosuppurative exudate persists within the alveoli
- Resolution (/death)
- In uncomplicated cases the alveoli are enzymatically digested to produce
granular semifluid debris that is resorbed, coughed up, or organised by
fibroblasts
GP NOTEBOOK SAYS:
Investigations:
- Chest X-ray
- Full blood counts
- Urea and electrolytes
- Sputum and blood cultures (look for pneumococcus, M. tuberculosis)
- Further investigations can include serology for atypical organisms
Treatment
- Community acquired:
- Amoxicillin (500mg three times daily)
- Erythromycin (500mg ttd) if allergic
- If atypical pneumonia is expected then add erythromycin or another
macrolide, if staph is suspected, add flucloxacillin
- Hospital acquired
- Broad spectrum cephalosporin (e.g. cefotaxime, ceftazidime)
- Metronidazole if anaerobic infection
*Note, this treatment plan is for lobar and lobular pneumonia
Complications:
- Hospital acquired form is most deadly
- Complications include empyema (pus in lung or pleural cavity), lung abscess,
bronchiolitis obliterans, acute respiratory distress syndrome and sepsis
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64. Lobular pneumonia. Etiology, pathogenesis and pathomorphology
In lobular (broncho) pneumonia the foci of inflammatory consolidation is distributed in

patches throughout several lobes, frequently bilateral and bases. The symptoms of
lobular pneumonia are the same as lobar pneumonia, main etiological causes are:
- S. aureus
- H. influenza
- P. aeruginosa
- E. Coli
- K. pneumoniae
- Proteus spp
Lobular pneumonia is more common in elderly and young patients, and is more
commonly hospital acquired than community acquired.
Pathomorphologically, the lung substance immediately surrounding the areas of

consolidation is usually hyperemia and edematous, but other areas of the lung are
generally preserved. Pleural involvement is less common than in lobar pneumonia, and
the histologic reaction consists of focal suppurative exudate that fills the bonchi,
bronchioles and adjacent alveolar spaces, but there is no fibrin.
65. Interstitial and viral pneumonia. Etiology, pathogenesis, microscopic & gross
pathomorphology
Interstitial pneumonia
Interstitial pneumonia (aka Nonspecific interstitial pneumonia) is a rare disorder affecting the
alveoli, it is a a type of interstitial lung disease (other types include idiopathic pulmonary
fibrosis and nonspecific interstitial pneumonitis (this is autoimmune)).
Interstitial pneumonia is a chronic idiopathic bilateral lung diseases. It can be one of two
forms, a cellular pattern (with mild chronic interstitial inflammation in uniform pattern) or a
fibrosing pattern (with patchy interstitial fibrosis).
Patients will present with cough of several months, possibly with dyspnea, fatigue and
clubbing.
Viral pneumonia
Viruses such as influenza A and B, respiratory syncytial virus and human parainfluenza
virus (in children) can all cause pneumonia (care viral agents include Adenovirus and
SARS).
Viral pneumonia is generally community acquired pneumonia, all pathogenic and

morphologic features tally with the normal bacterial pneumonia forms, just rehash this….this
is a stupid question!
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66. Acute respiratory distress syndrome. Etiology, pathogenesis, pulmonary

pathomorphology
Acute respiratory distress syndrome (ARDS) is caused by diffuse alveolar capillary and
epithelial damage, causing rapid onset respiratory insufficiency, cyanosis and
hypoxemia that results in multiorgan failure and death. Histologically, we see diffuse
alveolar damage that can occur as a result of direct or indirect insult to the lungs. There
is additionally a newborn respiratory distress syndrome, but this is separate, caused by
deficiency of surfactant.
Etiological causes are:

- Direct
- Pneumonia and aspiration of gastric contents most commonly
- Pulmonary contusion, fat embolism, near drowning, inhalational injury and
reperfusion injury after lung transplant more rarely
- Indirect
- Sepsis and severe trauma with shock commonly
- Cardiopulmonary bypass, acute pancreatitis, drug overdose, transfusion of
blood products and uremia more rarely
The Pathogenesis is summed up below:

- Alveolar-capillary membrane is formed of microvascular endothelium and alveolar
epithelium
- The integrity of this barrier in ARDS is then broken causing increased vascular
permeability and alveolar flooding leading to loss of diffusion capacity, widespread
surfactant abnormalities caused by type II pneumocytes.
- The damage to the cells and subsequent widespread release of inflammatory
mediators leads to endothelial activation and activation of neutrophils in pulmonary
capillaries
- The large number of neutrophils is visible on the slide
Pulmonary pathomorphology
- In the acute phase, lungs are dark red, firm, airless and heavy, microscopic
examination shows capillary congestion, necrosis of alveolar epithelial cells, and
intra-alveolar edema and hemorrhage.
- Most characteristically, observe hyaline membranes lining the distended
alveolar ducts
- In the organisation stage, we see proliferation of type II pneumocytes
- Resolution is unusual, commonly there is organisation of the fibrin exudates causing
intra-alveolar fibrosis and thickening of the alveolar septa
67. Pulmonary emphysema: classification, etiology, pathogenesis. Chronic

obstructive diffuse emphysema
Emphysema is the abnormal enlargement of of the air spaces due to the destruction of
alveolar walls, without fibrosis. Emphysema is most commonly associated with smoking,
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and very often occurs with chronic bronchitis, the combination of the two diseases being
Chronic Obstructive Pulmonary Disorder (COPD).
Classification is based on anatomic distribution within the lobule:

- Centriacinar (centrilobular) emphysema
- Central or proximal parts of acini are affected, while distal ones are spared
- Panacinar (panlobular) emphysema
- Acini are uniformly enlarged, affecting all of the alveoli
- Distal acinar (paraseptal) emphysema
- The proximal parts of the acini are normal, while the distal part is involved
- Irregular emphysema
- Irregular pattern of acinar damage
Etiology and pathogenesis

- Exposure to toxic substances are inhaled, and induce ongoing inflammation with
accumulation of neutrophils, macrophages and lymphocytes in the lung
- elastases , cytokines and oxidants are released causing epithelial injury and
proteolysis of the ECM
- Elastin degradation products further increase inflammation
- A genetic loss of alpha 1-antitrypsin exacerbated the issue
Diagnosis and classification is based on macroscopic appearance of lung, with diagnosis

under the microscope of alveolar destruction without fibrosis leading to enlarged air spaces.
The loss of elastic tissue in the alveoli means their air cannot be properly expelled from
alveoli, this makes it an obstructive disease.
GP NOTEBOOK SAYS
- Treatment is the same as COPD above
68. Pulmonary emphysema: acute, compensatory, focal, interstitial and senile

emphysema
Conditions related to emphysema

- Compensatory emphysema
- Alveoli compensate for damage to lung parenchyma by dilation and attempt to
improve lung function. Also known as compensatory overinflation.
- Obstructive overinflation
- Obstruction of the bronchi, causes lung expansion due to trapped air, often
caused by FB or tumour
- Bullous emphysema
- Any emphysema that produces large subpleural blebs (spaces greater than
1cm in the distended state) which represent localised forms of emphysema
- Interstitial emphysema
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- Air enters CT stroma of the lung, mediastinum and subcutaneous tissue. This
can occur spontaneously with sudden alveolar pressure increase (e.g. violent
coughing that results in a tear).
- Air can then travel in subcutaneous tissue and literally can cause patient to
swell up like a balloon (commonly around the head and/or neck)
69. Chronic obstructive pulmonary disease. Clinicopathological forms.

Pathomorphological changes in the lungs and heart
COPD is a type of irreversible obstructive lung disease characterised by long-term

poor airflow with dyspnea, cough and sputum production. It is a combination of chronic
bronchitis and emphysema (see above questions that explain each condition in turn).
Smoking is the principal cause of COPD, as is clear from the clear relationship between
smoking, emphysema and chronic bronchitis.
Pathologically, we see emphysema (abnormal enlargement of air spaces distal to the

terminal bronchiole and destruction of alveolar walls without fibrosis) and chronic
bronchitis (hypertrophy of the goblet cells and metaplasia of the pseudostratified epithelium
on the bronchi).
The earliest pathologic changes that are focal collections of brown-pigmented

macrophages in the respiratory bronchiole and sparse infiltrate of neutrophils and
lymphocytes in the walls of the terminal bronchi. This process will continue until the
almost complete mucous plugging of various distal airways, squamous cell metaplasia,
goblet cell hyperplasia and smooth muscle hypertrophy.
COPD also causes increased vascular resistance, this increases pulmonary pressure
(pulmonary hypertension) and causes right sided heart failure due to the increased effort
(although not before right sided hypertrophy occurs). This is known as cor pulmonale.
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70. Atelectasis - types. Pathomorphology. Acute massive pulmonary collapse

(post-surgical atelectasis).
Atelectasis is the collapse of part or all of the lung caused by inadequate expansion of air
spaces (derived from ‘ateles‘ and ‘ektasis‘ meaning incomplete expansion). There are three
types:
- Resorption atelectasis
- Occurs when an obstruction prevents air from reaching distal airways and air
that is already there becomes resorbed
- Compression atelectasis
- Occurs when something (usually fluid, blood or air in pleural cavity) collapses
the lung
- Most common in pleural effusion
- Contraction atelectasis
- Occurs when there is general or local fibrosis that contracts the lung
Diagnosis is best done on chest X-ray, you’re looking for white out and to observe the
displacement of central structures towards the affected lung. Treatment is based on the
underlying cause (compression, remove compressive element, resorption, remove blockage
etc).
Acute massive pulmonary collapse (post-surgical atelectasis)

Also known as acute atelectasis, may occur as a postoperative complication or as a result
of surfactant deficiency in neonates (leads to infant respiratory distress syndrome). In
surgical cases, the main risk factors are:
- Age
- Smoking
- General anesthetic
- Duration of surgery
- Pre-existing lung or neuromuscular disease
- Prolonged bed rest
- Poor post op pain control (causing shallow breathing)
71. Hypersensitive pulmonary diseases. Bronchial asthma. Eosinophilic

pneumonia. Allergic granulomatosis (Churg-Strauss syndrome)
Asthma
Asthma is a chronic inflammatory bronchial disease characterised by reversible
heezing, breathlessness,
obstruction of the airway. It causes recurrent episodes of w
chest tightness and cough, often at night or early morning. It is a hypersensitive
disorder, where inflammatory cells over react to antigens such as house dust mites (dust),
irritants such as smoke, stress or exercise.
Asthma can be atopic (allergen sensitization, often with eczema, allergic rhinitis etc) and
nonatopic, although bronchospasm can be caused by any of the antigens above, atopic
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types tend towards type 1 hypersensitivity reactions (re-exposure reaction with Ig E

antibodies).
Pathogenesis
- Inflammation involves many cell types and inflammatory mediators but helper T (type
2) cells are of critical importance
- The atopic type sees an overaction of TH2 cells against environmental antigens,
which triggers a chain reaction producing Ig E antibodies and production of B cells,
this in turn triggers bronchoconstriction and increased mucus production.
- Atopic Asthma has a significant genetic component, as well as environmental (60%
genetic link)
- Non-atopic asthma does not have evidence of allergen sensitization and a FH is less
prevalent, generally respiratory infections due to viruses and inhaled air pollutions are
the culperates.
Pathology
- Bronchi show edema, hyperemia of mucosa and infiltration of mucosa by mast cells,
eosinophils and lymphocytes (TH2).
- Airway is thickened by deposition of type III and type V collagen below basement
membrane in chronic cases, this causes bronchial airway remodelling
Treatment:
- Two aspects, control of symptoms (rescue treatments) and prevention of
exacerbations.
- Rescue treatments - taken as required in flare up
- Beta adrenergic agents
- E.g. albuterol
- Anticholinergics
- E.g. Tiotropium Bromide & Ipratropium bromide
- Controller treatments - taken daily to prevent flare ups
- Inhaled corticosteroids
- E.g. beclomethasone, budesonide, fluticasone
- Antileukotrienes
- Long acting beta-agonists
- Theophylline
- Systemic corticosteroids
- Monoclonal antibody treatment
Treatment for Status Asthmaticus goes beyond the scope of this document, see Internal
Medicine: Pulmonology
Eosinophilic pneumonia
A disease where eosinophils accumulate in the alveolar spaces (remember, pneumonia
is a general term of exudative fluid the lungs). Common symptoms are in line with other
pneumonias, cough, fever, dyspnea and night sweats.
Classification is based on etiology:
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- Parasitic infection
- Cancer
- Autoimmune
- Idiopathic (acute and chronic)
Think of this as immune related pneumonia, basically, antigen, causes immune reaction,
eosinophils invade alveoli, bob’s your uncle!
Allergic granulomatosis
An extremely rare AI condition that causes inflammation of small and medium blood
vessels (vasculitis). It has three stages:
- Prodromal (early) - marked airway inflammation (similar to asthma)
- Hypereosinophilia - causes tissue damage to lungs and GI tract
- Vasculitis - eventually leads to cell death and can be life threatening
Image shows extravascular eosinophil infiltration of tissue
Treatment is strong glucocorticoid suppression of the immune system.
72. Pneumoconiosis. Etiology, pathogenesis, types, pathomorphological forms,

complications
Pneumoconiosis is a disease of the lungs due to inhalation of dust which in turn causes
fibrosis. The most common types are due to exposure to coal dust, silica and asbestos.
Only particles between 1-5 micrometers are likely to get to the distal airways, smaller than
this they fail to land, larger they are held up by the mucus. Coal dust is relatively inert and
requires a lot to be inhaled prior to any symptoms, meanwhile silica and asbestos are a lot
more reactive meaning that fibrotic reactions occur at lower concentrations.
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Pulmonary macrophages are key in initiation of fibrotic process, particles activate

inflamation and trigger fibrotic reaction. Tobacco smoke worsens the effect of all
pneumoconiosis conditions.
Coal workers pneumoconiosis

- Spectrum of diseases from asymptomatic anthracosis to simple coal workers
pneumoconiosis or progressive massive fibrosis
- In extreme cases with progressive lung fibrosis we see a risk of Cor Pulmonale and
restrictive lung failure
Silicosis
- Most prevalent chronic occupational disease in the world, caused by inhalation of
crystalline silica (in particular sandblasting and hard rock mining)
- Ingested silica particles cause activation and release of mediators by pulmonary
macrophages which can cause fibrosis
- Silicotic nodules in the lung are classically plate-to-blackened in the upper zones
of the lungs, under the microscope the silicotic nodules are concentrically arranged
hyalinized collagen fibers
Asbestosis
- Can be linked to
- Parenchymal interstitial fibrosis (asbestosis)
- Localised fibrous plaques
- Pleural effusions
- Lung carcinomas
- Malignant pleural and peritoneal mesotheliomas
- Laryngeal carcinoma
- There are two types of asbestos (serpentine and amphibole, the latter is the most
pathological)
- Present under microscopic examination are asbestos bodies (golden brown fusiform
rods with translucent center). Asbestosis begins at the lower lobes (unlike other
pneumoconiosis), often with pleural plaques being the most significant early
manifestation (these often contain calcium and are found on posterolateral aspect of
parietal pleura).
73. Primary tumours of the lung and pleura - benign & malignant. Histological and
macroscopic forms
Main types of primary malignant lung tumours:

- Non-Small-Cell lung cancer types
- Adenocarcinoma (40%)
- Squamous Cell Carcinoma (25-30%)
- Large cell carcinoma (10-15%)
- Small Cell Lung Cancer (Small Cell Carcinoma - 15-20%)
Adenocarcinoma
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- Genes that mutate to allow adenocarcinoma development: EGFR, ALK, ROS, KRAS
- Smoking is not a major risk factor, commonly occurs in young, non-smoking women.
- May occur as central lesion, but more commonly peripherally located
- They grow slowly, and form smaller masses than other subtypes, but metastasise
earlier
- Histological form may be acinar ( gland-forming), papillary, mucinous or solid type.
- Precancerous lesion is adenocarcinoma in situ, with hyperplasia and fibrosis of
alveolar walls
- Diagnosis through direct observation of enlarged glands or increased mucin
production. If this is not observed, should perform immunohistochemistry to observe
TTF antibodies
Squamous Cell Carcinoma

- Gene that mutates to allow carcinoma is TP53
- Main etiological cause is smoking ( 99% of patients are smokers)
- Lesions tend to arise centrally in major bronchi, close to the hilum, causing
central necrosis and cavitation
- Often produce productive cough, the sputum of which may contain cancerous cells
which can be examined under a microscope.
- SCC’s produce keratinisation of cells, with keratin pearls on histological examination.
These prove the diagnostic gold standard, without this, observe antibodies P40 and
cytokeratin 5 & 6.
- Pre cancerous lesion is squamous metaplasia or dysplasia of bronchial epithelium,
which then transmissions to carcinoma in situ.
Large Cell Carcinoma

- Can appear in any part of the lung, presents as a non-productive cough with
weight loss
- It is diagnosis by exclusion, as the tumour cells lack the characteristics that would
define them as other non-small cell carcinomas or small cell carcinomas.
- Comprises 5-10% of all lung cancers
Small cell carcinoma

- Genes that mutate are TP53, Retinoblastoma gene (RB) and Transcription factor
coder MYC
- Lesions generally located centrally, but can be peripheral
- Typical growth is subepithelial, and so invisible underneath the mucosa of the
bronchi, diagnosis may have to be via a blind biopsy
- Often metastasizes into the mediastinum, with enlarged lymph nodes present
- Highly proliferative tumour, surgery not an option, chemotherapy and radiotherapy
are prefered
- Unlike in NSCLC there is no mucin, and neuroendocrine markers are usually present
Benign lesions
Most common among the benign lesions of the lung is the Hamartoma, a neoplasm that
occurs throughout the body, but most commonly in the lung, and accounts for 75% of benign
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lung tumours. The majority form from the CT around the lung, 10% from the bronchi
epithelium. They are more common in men than women, and can affect lung function.
Treatment is generally surgical.
Pleural lesions
Almost always a secondary complication, primary pleural tumours are rare. Commonly
secondary to primary intrapleural infection. The most common primary neoplasm is a
malignant mesothelioma.
Malignant mesotheliomas are often preceded by extensive pleural fibrosis and plaque
formation. They can arise in parietal or visceral pleura, commonly associated with
asbestos and other occupational diseases. Macroscopically, typically we see a
yellow-white, firm gelatinous layer of tumour that obliterates pleural space. There are
three histological patterns;
- Epithelial
- Sarcomatous
- Biphasic
Gastrointestinal pathology
74. Diseases of esophagus: esophagitis, gastroesophageal reflux disease,
achalasia, diverticula, hiatal hernia. Esophageal tumors - benign & malignant
Esophagitis
- This is inflammation of the esophagus, below we list common forms of esophagitis
- Lacerations
- Most common form of ulcerative esophagitis is Mallory-Weiss tears, often
associated with severe retching and vomiting that may be a result of
excessive alcohol.
- Prior to vomiting there is usually muscular relaxation, it is thought this fails
during prolonged vomiting which causes the esophageal wall to stretch and
tear
- In Mallory-Weiss syndrome tears are generally superficial, in the more severe
Boerhaave syndrome however, there are transmural esophageal tears
which are a catastrophic event
- Chemical and infectious esophagitis
- The stratified squamous mucosa of the epithelium may be damage by
irritants such as alcohol, acids, alkalis, hot fluids and heavy smoking.
- Generally such esophagitis only causes pain, particularly pain with
swallowing (odynophagia)
- Morphologic changes see accumulation of neutrophils, hyperemia and
ulceration
- Infectious forms generally only occur in immunocompromised individuals
- Reflux esophagitis
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- Stratified squamous epithelium is sensitive to acid, where we have reflux of

gastric contents into lower esophagus (GERD) we get the most frequent
cause of esophagitis.
- Pathogenesis is based around conditions that decrease cardiac sphincter or
increase abdominal pressure including alcohol and tobacco use, obesity and
CNS depressants.
- Reflux causes basal zone hyperplasia with hyperemia and eosinophils in
the mucosa
- Clinical features are that of heartburn, dysphagia and occasionally
sour-tasting gastric contents
- Most notable complication is Barrett Esophagus, where metaplasia occurs,
converting squamous cells to goblet cells and significantly increasing the risk
of adenocarcinoma (30-100x increase).
Achalasia
Esophageal is an esophageal motility disorder where the smooth muscle fails to relax
(literally, a- + -chlasia = no relaxation), causing lower esophageal sphincter to remain
closed. Clinical picture presents with dysphagia, reflux, and sometimes chest pain.
Most common form is primary achalasia which is idiopathic, due to the failure of distal
esophageal inhibitory neurons. Secondary types can occur due to esophageal cancer,
Chagas disease and a few others.
Diverticular
A diverticulum is an outpouching, they can be true (involving all layers of the structure), or
false, not involving the adventitia (e.g. only the submucosa and mucosa). In the
esophagus there are three areas diverticular can occur:
- Pharyngoesophageal
- Midesophageal
- Epiphrenic
One important esophageal diverticula is Zenker’s diverticulum. It is a
pharyngoesophageal diverticulum that sits just above the cricopharyngeal muscle
caused by excessive pressure in the lower pharynx which causes this pseudo diverticular.
Symptoms include dysphagia, regurgitation, cough and halitosis.
Hiatal hernia
Here the stomach slips through the diaphragm into the chest, it can often cause GERD
or laryngopharyngeal reflux. Risk factors include obesity and old age with symptoms
including heartburn, dysphagia, and in some cases dyspnea and pain.
Tumours
The majority of esophageal tumours are adenocarcinoma and squamous cell carcinoma
- Adenocarcinoma
- Often as a result of Barrett esophagus and chronic GERD
- Barretts esophagus sees metaplasia of SCE to goblet cells
- Much more common in men and whites, linked to poor diet.
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- Symptoms include chest pain, dysphagia, weight loss and vomiting

- Survival less than 25% once symptoms begin
- Squamous Cell carcinoma
- Risk factors include alcohol, tobacco, poverty, achalasia and very hot drinks,
much more common in african americans
- Can be found throughout the esophagus (not limited to distal ⅓ as adenomas
are)
- Invasion into basement membrane is key diagnostic feature
- Clinical manifestation is as with adenocarcinoma
75. Acute and chronic gastritis - etiology, pathogenesis, types; microscopic &
gross pathomorphology
Acute gastritis
This is transient mucous inflammation that may be asymptomatic or cause epigastric pain,
nausea and vomiting.
The stomach is a highly acidic environment, gastritis can occur when either the protective
mechanisms of the stomach fail, or there is an increase in acid production. Protection
mechanisms include:
- Foveolar cells produce Mucin which prevents direct contact with the epithelium
- Bicarbonate ion secretion by epithelial cells create neutral layer
- Rich vascular supply delivers oxygen, bicarbonates and nutrients, while removing
acid that has diffused into the lamina propria
Disruption to any of these elements (e.g. reduced mucin synthesis due to age) increases
susceptibility, as do drugs such as NSAIDs which reduce bicarbonate availability, and
ingestion of harsh chemical elements.
On histologic examination, mild acute gastritis is largely invisible, as there is only slight
edema and vascular congestion, scattered neutrophils may be present , and any neutrophils
in contact with the epithelial cells is abnormal in all parts of the GI system and signifies
active inflammation. In more extensive inflammation erosion may be present with
purulent exudates and hemorrhage.
Chronic gastritis
Signs and symptoms typically less severe but more persistent than acute form. Nausea and
upper abdominal pain can present. Most common cause is infection of H.pylori (see
below) with atrophic gastritis due to autoimmune causes making up the remainder of
cases.
H. Pylori increase the acid secretion and weaken defences in the stomach and as such
increase risk of gastritis and ulcers. H. Pylori create urease, elevating local gastric pH
and therefore allows it to survive, while simultaneously releasing toxins which increase
gastric secretions.
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Over time chronic gastritis can become pangastritis with multifocal atrophic gastritis and
increased risk of adenocarcinoma.
76. Gastric and duodenal peptic ulcer - etiology, pathogenesis, microscopic &
gross pathomorphology, complications
Ulcers are the continued process of gastritis, be that acute or chronic. Where gastritis
occurs, it can then lead to an ulcer (defined as the point at which the muscularis mucosa
has been reached), which in turn can lead to perforation.
Acute peptic ulceration

- A complication of therapy with NSAIDs and severe stress, there are three types of
lesion
- Stress ulcers - commonly patients who are critically ill
- Curling ulcers - occur in proximal duodenum and associated with burns
- Cushing ulcer - in stomach, duodenum or esophagus, generally in patients
with intracranial diseases
- Thought to be due to systemic acidosis
NSAID induced ulcers are caused by direct chemical irritation and cyclooxygenase
inhibition, while other conditions such as stress ulcers and sepsis are thought to relate to
decreased blood circulation in the gut.
Morphologically, lesions vary in depth and shape, typically they are rounded and less than
1cm in diameter, blackened by acid with necrotic debris. Single lesions are possible but
often multiple occur. Healing can take days or weeks after etiological factors are removed.
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Peptic ulcer disease (chronic peptic ulceration)

- Associated with chronic NSAID use or H.pylori and is rapidly become the most
common cause of ulcers
- Most common in proximal part of the duodenum or, less likely in gastric antrum
- May also occur in duodenum as part of GERD
- For full pathogenesis see PG of Chronic gastritis, this is the natural continuation
- 80% are solitary, lesions less than 0.3cm usually shallow, greater than 0.6cm in
diameter generally deeper. The base of the ulcer is generally smooth and clean
thanks to peptic digestion
- Ulcers are recurring, cause epigastric pain and can cause complications such as iron
deficiency anemia, frank hemorrhage or perforation. Nausea, vomiting and bloating
may all be present.
77. Benign gastric tumors - of epithelial and mesenchymal origin. Stromal tumors -
GIST
The list of benign gastric tumors is:

- Gastric polyps
- Fundic gland polyps
- Gastric adenoma
- Lipomas
- Leiomyomas
Two potentially malignant ones are:
- Carcinoid tumour
- Gastrointestinal stromal tumor (GIST)
Gastric polyps (epithelial tumour)

- These are nodules or masses that project above the mucosa
- May be as a result of hyperplasia, inflammation, ectopia or neoplasia
- There are different types of polyps
- Inflammatory and hyperplastic polyps
- Most common by far, affect those 50-60
- Usually have chronic gastritis with H.pylori
- Frequently multiple, stable, smooth, ovoid and less than 1cm
- Microscopically polyps have irregular, cystically dilated foveolar glands
and lamina propria is edematous
- Polyps larger than 1.5cm have increase risk of dysplasia, a
precancerous in situ lesion
- Fundic gland polyps
- Sporadic and in persons with familial adenomatous polyposis (FAP)
- No neoplastic potential
- Occur as a result of proton pump inhibitor use
- May be asymptomatic, or cause vomiting and nausea
- Gastric adenoma
- 10% of cases, occur in background of chronic gastritis with atrophy
- Risk of adenocarcinoma development, bigger polyp, bigger risk
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- (see gastric adenoma section below)
Gastric lipoma (mesenchymal tumour)

- Derived from fat tissue, they are rare (less than 1% of gastric neoplasms)
- May present with upper GI bleeding, dyspnea or gastric obstruction
- Histology shows adipose cells with fibrous capsule
Gastric Leiomyoma (mesenchymal tumour)

- Rare, asymptomatic, generally found incidentally
- Derived from smooth muscle of muscularis propria or lamina muscularis mucosa of
stomach
Carcinoid tumour (neuroendocrine tumour)

- Of neuroendocrine origins (e.g. endocrine pancreas)
- Most are asymptomatic however all have malignant potential and about 10% secrete
hormones (most commonly serotonin, causing flushing, diarrhea, wheezing,
abdominal cramps and peripheral edema).
- In the GI system, Carcinoid tumours are most common in the appendix or small
intestines.
- Known as carcinoid as they are slower growing than carcinomas
- They created small yellow polypoid lesions that can cause kinking of bowel and
obstruction. Histologically the are composed of islets, strands and glands.
- The most important prognostic factor is the location
- Foregut - stomach + proximal duodenum rarely metastasize and are cured by
resection
- Midgut - jejunum + ileum tend to be more aggressive
- Hind gut - appendix and colorectum - almost always benign, although rectal
forms generally produce polypeptide hormones
Gastrointestinal stromal tumour (GIST) (mesenchymal tumour)

- Most common mesenchymal tumour of the abdomen, more than half in the stomach
- More common in males - 80% have mutatio of tyrosine kinase c-KIT gene
- Form from solitary, well circumscribed submucosal mass, metastases may be
multiple small serosal nodules or larger nodules in the liver although spread outside
abdomen is uncommon. Histologically may have elongated spindle cells or plump
epithelial cells
- Clinical symptoms are related to location and size of the mass
78. Gastric carcinoma: etiology and pathogenesis. Precancer. Microscopic & gross
pathomorphology. Clinic-morphological methods of early diagnostics
There are three types of ‘gastric cancer’, Gastric carcinomas, lymphomas and GIST (may
or may not be considered malignant). Here we consider Gastric carcinoma, specifically,
Gastric adenocarcinoma, the most common malignancy of the stomach (90%) with early
symptoms that resemble chronic gastritis.
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Gastric adenocarcinoma is up to 20 times higher in Japan, Chile, Costa Rica and Eastern
Europe. Areas like Japan do mass endoscopic screening programs to identify early gastric
cancer.
Etiology and pathogenesis

- Has a genetic component (loss of E-cadherin function with mutation of CDHI gene)
- Association with H. pylori which promotes chronic gastritis, conferring increased risks
- 10% of gastric adenocarcinomas are associated with Epstein-Barr virus
Gastric adenomas can be classified based on location as well as morphology. We separate

them into intestinal and diffuse types. Diffuse gastric c ancers have an infiltrative growth
pattern with discohesive cells and large mucin vacuoles that create a signet ring cell
morphology. These tumours invoke desmoplastic reactions that stiffen gastric wall and can
cause thickened wall known as linitis plastica. Meanwhile intestinal type adenocarcinoma
grow along cohesive fronts to form an exophytic mass or an ulcerative tumour.
Precancer lesion
- There is no precancerous lesion for the diffuse type
- The intestinal type is preceded by a dysplastic lesion with adenomas. It is
closely associated with atrophic gastritis and intestinal metaplasia
The depth of invasion and extent of metastasis remain the most powerful indicator of
prognosis. Local invasion is characteristic and can have a high survival rate.
Early diagnosis is vai Gastroscopic exam, later diagnosis with upper GI X-ray or CT. Recent
advances in china have looked at a breathalyzer style breath test which seems to be able to
identify stomach cancer based on exhaled chemicals.
79. Chronic enterocolitis - types. Ulcerative colitis, Crohn disease, Whipple

disease. Microscopic & gross pathomorphology
Enterocolitis (aka colenteritis) just means inflammation of the digestive tract, involving the
small and large intestine. It can be viral, bacterial, fungal, parasitic or autoimmune. The
common symptoms are malabsorption, diarrhea, nausea, vomiting, abdominal pain,
fever, and possibly blood in the stool.
Common bacteria are Salmonella, Shigella, E. coli, Campylobacter, common viruses are
enterovirus, rotavirus, norwalk virus, adenovirus.
As well as dividing types based on etiology, we can add the following types:
- Necrotizing enterocolitis
- Necrosis of the intestine occurs with inflammation, most common in
premature babies. General GI symptoms as expected, exact cause is unclear,
but is thought to combine poor blood flow and infection
- Antibiotic-associated enterocolitis (Pseudomembranous enterocolitis)
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- Antibiotics clear out normal gut bacteria and Clostridium difficile spreads
causing inflammation throughout the gut. Can cause watery diarrhea as well
as other expected symptoms
- Hemorrhagic enterocolitis
- Caused by strains of E.coli that produce Shiga toxin causing bloody diarrhea
and other complications
- Organisms often transferred via unpasteurized milk
Ulcerative Colitis & Crohn's

Together these form IBD, inflammatory bowel disease. It is
chronic and arises from inappropriate mucosal immune
activation.
Ulcerative colitis is limited to the colon and rectum,

extending only into the mucosa and submucosa. It’s
progression is stepwise, not missing out sections. However
Crohn's disease can affect any part of the GI tract, is
frequently transmural and does skip, it doesn’t have to be
continuous.
Both disorders are more common in women, and more

common in the west. The exact cause of IBD is uncertain,
however mst believe it comes from errors in interaction
between intestinal microbiota, intestinal epithelial dysfunction and aberrant mucosal immune
responses. Primary factors we shall consider:
- Genetics - risk is increased when family member has disease (NOD2 mutation
increases susceptibility)
- Mucosal immune response - immunosuppressors help with symptoms, suggesting
the mucosal immune response is of central importance to the pathogenesis
- Epithelial defects - defects in tight junctions present in Crohn's (NOD2
polymorphisms)
- Microbiota - data suggests it’s important but we don’t know how
Morphology
- Crohn's
- Most common sites are terminal ileum, ileocecal valve and cecum
- Disease limited to small intestine in 40% of cases
- Presence of multiple, separate, delineated areas, known as skip lesions
- Lesions do however coalesce into elongated serpentine ulcers along the axis
of the bowel with fissures frequently developing and the formation of a
cobblestone appearance
- The intestinal wall thickens due to transmural edema, inflammation,
fibrosis and hypertrophy of muscularis propria
- Microscopic examination reveals clusters of neutrophils within a crypt known
as crypt abscesses, ulceration is common, Paneth cell metaplasia may
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occur in left colon (where paneth cells are normally absent). Noncaseating
granulomas are also found in 35% of patients
- Ulcerative colitis
- Always involves rectum and extends proximally continuously
- Disease of the entire colon is pancolitis
- Gross morphology shows broad-based ulcers with granular appearance
- Regenerating mucosa often bulge into luman creating pseudopolyps
- Mucosal atrophy may also develop
- Unlike in Crohn's mural thickening is absent, serosal surface is normal and
there are no strictures
- Histologically, very similar to Crohn's
Whipple’s disease
- A rare systemic infectious disease caused by Tropheryma whipplei which causes
malabsorption. Weight loss, diarrhea, joint pain and arteritis are all common
symptoms
- T. whipplei is common in farmers and those exposed to soil and animals, suggesting
this as its origin
- Immunocompromised is thought to be required in order to be susceptible
- Often occurs in chronic form, with relapsing episodes of non-destructive seronegative
arteritis
- Endoscopy of small intestine can show pale yellow shaggy mucosa with
erythematous eroded patches
80. Intestinal obstruction (ileus) types. Mesenteric thrombosis.

Complications
Intestinal obstruction
Collectively, hernias, intestinal adhesions, intussusception and
volvulus account for 80% of all mechanical obstructions, while tumours
and infarction are generally the rest. Clinical picture includes pain,
distention, vomiting and constipation. Surgery is usually required.
Hirschsprung disease (1 in 5000 births) is a congenital disorder where

the enteric neural plexus fails to properly develop causing loss of
submucosal plexus and myenteric plexus meaning peristalsis is
absent. Along with congenital hernias, this is one of the more common
intestinal obstructions in newborns.
Mesenteric thrombosis
This is a blood clot in one of the veins draining or arteries supplying the intestines, it can
affect the splenic vein, or superior or inferior mesenteric vessels. Clots to these veins can
occur due to abdominal injury, clotting disorders, inflammatory bowel diseases, pancreatitis,
liver cirrhosis and tumours.
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Symptoms will include abdominal pain, bloating, diarrhea, vomiting and possibly fever with
bloody stools.
Where we see an arterial blockage we will see ischemia and gangrene of the bowel wall.
81. Peritonitis - etiology, patho morphologic forms according to the types of

inflammation
Inflammation of the peritoneum, that is, the lining of the inner wall of the abdomen and
connective tissue that covers the abdominal organs.
Etiology
- Perforation of GI tract
- Pancreatitis
- Pelvic inflammatory disease
- Stomach ulcer
- Cirrhosis
- Ruptured appendix
Presents with severe acute abdominal pain, abdominal tenderness and abdominal
guarding. Blumberg sign (rebound tenderness) is another clear symptom. Can be localized
to part of the peritoneum or involve the whole peritoneum.
Can be described as being primary (due to direct bacterial infection, transmitted through
blood, lymph or direct invasion) or secondary ( due to pre existing acute abdominal
condition).
As we mentioned, peritonitis can be diffuse (aka Suppurative peritonitis) or local (local

abscess forming). As the infection occurs there is significant fibrosis within the
peritoneum with the production of fibrin exudates as part of the host defence in order to
limit the spread of bacteria and maintain the infection in one part of the peritoneum. Whether
this prevails and contains the bacteria into an abscess will depend on the extent of bacteria
in the abdomen.
82. Tumors of the small intestine: epithelial/mesenchymal, neuroendocrine,

lymphomas
Tumours of the small intestine are rare, usually single, and can be malignant or benign.
Symptoms of all SI tumours are generic, stomach pain, nausea, weight loss, occasional
rectal bleeding.
Malignant tumours
- Adenocarcinomas
- These develop from adenomas (precursor), mostly at the ampulla of the
duodenum. Chron’s and celiac are risk factors
- Intestinal Lymphoma
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- Complication of celiac, and can occur in immunodeficiency syndromes

- Leiomyosarcoma
- Tumour arises from smooth muscle wall of the intestine, can also arise from
benign leiomyoma
- Neuroendocrine
- Includes Carcinoid, Gastrin cell & Somatostatin cell tumours
Benign tumours
- Leiomyoma
- Adenomas
- Lipomas
- Hemangiomas
- Neurogenic tumours (most commonly neurofibroma)
83. Appendicitis - types according to etiology, pathogenesis and forms of

inflammation. Tumors of the appendix - epithelial, neuroendocrine
The appendix is a normal true diverticulum of the cecum, it is prone to chronic and acute
inflammation.
Acute appendicitis
- Most common in adolescents, 7% prevalence across life
- Etiology due to progressive increases in intraluminal pressure that compromises
venous outflow. Many cases are also associated with luminal obstruction (by fecaliths
or gallstones)
- Subserosal vessels are congested, with perivascular infiltrate in all layers of the wall.
Gross visual changes show a dull, granular appearing erythematous surface. In
more severe cases focal abscesses may form (acute suppurative appendicitis)
which may create hemorrhagic ulcerations and gangrenous necrosis, often
followed by rupture
- Clinical observation is localised pain in the right lower quadrant with nausea, vomiting
and low grade fever. Deep tenderness is found at McBurney’s point, known as
McBurney's sign.
Tumours of the appendix

- Most common is the carcinoid tumor, often discovered incidentally
- Adenomas or non-mucin-producing adenocarcinomas can also occur in the appendix
and may cause obstruction and enlargement that mimics acute appendicitis
84. Benign tumors and carcinoma of the colon. Etiology & pathogenesis.
Microscopic & gross pathomorphology. Role of fibro colonoscopy in early
diagnostics
Polyps are common in the colon, those without stalks are sessile polyps, those with stalks
are known as pedunculated polyps. Polyps can be neoplastic or non-neoplastic. The
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most common neoplastic polyp is adenoma, which can progress to cancer. Let’s look at
the classifications below:
- Inflammatory
- Part of solitary rectal ulcer syndrome
- Purely inflammatory lesion
- Clinical triad of rectal bleeding, mucus discharge and inflammatory lesion on
anterior rectal wall
- Hamartomatous polyps
- Occur sporadically, comprised of genetic and acquired syndromes
- Hamartomas are disorganized tumour like growths composed of mature cells
- Types;
- Juvenile polyps - most common form of Hamartomatous polyp.
Usually in rectum. Most manifest with rectal bleeding.
- Peutz-Jeghers syndrome - AD disorder defined by many GI
hamartomatous polyps and mucocutaneous hyperpigmentation that
increases malignancy risk.
- Hyperplastic polyps
- Epithelial proliferations, common in 60s and 70s
- Thought to be a delayed shedding of surface epithelial cells causing a pile up
- No malignant potential
- Most commonly found in L ascending colon, usually <5mm diameter
- Contain mature goblet cells and absorptive cells
- Adenomas
- Most common cause of polyp formation
- Are a precancerous lesion to adenocarcinomas
- Characterised by presence of epithelial dysplasia
- Common age 50+ (colorectal screening occurs at this age)
- Typical finding is pedunculated or sessile polyp 0.3-10 cm in diameter with
velvet or raspberry texture due to abnormal epithelial growth. Epithelial
dysplasia is the most important histological finding.
- Can be classified as tubular, tubulovillous or villous based on architecture
- Adenocarcinomas
- Most common malignancy of the GI tract, more than 130,000 new
cases/year with 55,000 deaths.
- Genetic involvement which causes increased WNT signalling and
microsatellite instability (associated with defects in DNA mismatch repair)
- Loss of APC gene function which regulates beta catenin of the
WNT pathway
- Adenocarcinomas can be found throughout the colon, proximal colon tumours
often grow as polypoid exophytic masses, while distal colon tumours tend to
form ‘napkin ring’ constrictions and luminal narrowing (think apple core sign).
- Most tumours are composed of tall columnar cells, resembling dysplastic
epithelium from adenomas. Some may be mucin producing
- Anemia and blood in feces are two of the big indicators. Depth of invasion and
presence of metastasis are two big indicators for prognosis
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Familial neoplastic syndromes

These are genetic syndromes associated with colonic polyps and increased risk of colon
cancer:
- Familial adenomatous polyps
- AD disorder (APC gene mutation)
- Appears in teenage years with counts of 100+ polyps
- Morphologically indistinguishable from adenomas except excessive numbers
- Colorectal adenocarcinoma begins in 100% of patients not treated
- Hereditary nonpolyposis colorectal cancer
- HNPCC (aka Lynch syndrome)
- Caused by germline mutation of genes including MSH2 and/or MLH1
85. Primal and secondary (metastatic) tumors of the peritoneum
Rarer cancer (so rare not in the book).
Primary peritoneal tumours

The most common form is mesotheliomas, a simple squamoid malignancy that arises
from the lining surfaces of the peritoneal cavity. Has significant male predominance, and a
history of asbestos exposure.
Histologically, we see hard whitish nodules scattered over the peritoneal surface, these
nodules coalesce into plaques. Microscopically, we see extensive vacuolization,
psammoma bodies and the presence of hyaluronic acid without mucin.
A second type of peritoneal cancer is the Extraovarian primary peritoneal carcinoma.

Histopathologically similar to ovarian cancer, EOPPC is commonly a serous surface
carcinoma.
Secondary
- Metastasis can from from breast and lung
- Spread via direct invasion, lymphatic paths, intraperitoneal seeding and
hematogenous spread
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- Pseudomyxoma peritonei is form of secondary tumour that occurs due to the
rupture of a cystadenocarcinoma of the appendix or colon seeding carcinogenic cells
in the peritoneal surface
Hepatic and Pancreatic Pathologies

86. Acute and chronic viral hepatitis. Etiology & pathogenesis. Basic morphologic
classification. Microscopic and gross pathomorphology.
Hepatitis is the general term given to a specific histopathological pattern of hepatocyte

injury with inflammation (and scarring in chronic cases). First we shall give the
pathomorphological description that defines hepatitis, and then move on to the various
etiologies and breakdowns.
Gross morphology
- In mild acute states may only appear slightly mottled, in severe states may shrink
to 500g, become limp and red covered with a wrinkled baggy capsule.
- In chronic hepatitis there may be evidence of scarring or widespread nodularity
surrounding the scaring
- The entire liver may be involved or only patches
Microscopic morphology
- Mononuclear infiltrates predominate in all phases of most hepatic disease due to
the fact they invoke T-cell mediated immunity. As such the distinction between acute
and chronic (usually acute = neutrophils, chronic = monocytes) is based on pattern of
injury, with acute hepatitis often showing less inflammation and more hepatocyte
death
- Injury and inflammation can vary based on etiology. Hepatocyte injury has two forms:
- Ballooning degeneration (swelling) which eventually leads to cell rupture
with cells appearing to have dropped out, leaving a collagen reticular
framework behind
- Apoptosis where cells shrink and become intensely eosinophilic. When in the
parenchyma this is known as lobular hepatitis
- In severe cases we can see central portal bridging necrosis followed by even
worse parenchymal collapse
- In chronic cases we also expect to see a degree of patchy cellular regeneration. As
well as portal inflammation with mononuclear portal infiltrates.
- In most severe chronic cases scarring and nodule formation leads to the
development of cirrhosis with increased risk of malignancy
Now we shall consider some of the causes, firstly Viral hepatitis

- Hepatitis A
- ssRNA, fecal-oral contamination, 2-6 week incubation, never chronic, not
unusual in poor countries (endemic), virus not toxic to hepatocytes
- Hepatitis B
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- dsDNA, parenteral, sexual and perinatal transmission, 4-26 week incubation,

10% chronic
- Can cause acute hepatitis with recovery, non progressive chronic hepatitis,
progressive chronic hepatitis or can be benign. Has vaccine
- Microscopically, has all of the above mentioned features of hepatitis, as well
as showing the diagnostic ground glass cell (large, pale, granular cytoplasm
due to ballooning of endoplasmic reticulum).
- Hepatitis C
- ssRNA, parenteral, intranasal cocaine RF, 2-26 weeks, 80% chronic,
- Can cause acute or chronic hepatitis, but in acute stage is asymptomatic
often
- We see typical microscopic features listed above, as well as fatty change,
lymphoid infiltrates in portal tracts and bile duct injury
- Hepatitis D
- ssRNA, parenteral route, 5% chronic in coinfection, 70% in superinfection.
- Aka delta hepatitis virus
- Hep D can only replicate in presence of Hep B virus (which has HBsAg
antigen).
- We divide Hep D patients into:
- Acute coinfection - Hep B + Hep D exposure simultaneously
- Superinfection - chronic Hep B, followed by Hep D later
- Acute co infection patients generally recover no issues, super infected
patients generally die of severe chronic hepatitis.
- Hepatitis E
- ssRNA, fecal oral transmission, 2-8 weeks incubation, never chronic
- Endemic in india, largely self-limiting and harmless
Clinical features and outcomes for viral hepatitis

- Asymptomatic acute infection
- Acute hepatitis
- Fulminant hepatitis (acute liver failure from massive hepatocyte necrosis)
- Chronic hepatitis
- Chronic carrier
Other causes of hepatitis

- Other viral causes
- Epstein Barr virus may cause mild hepatitis during acute phase
- Cytomegalovirus infection
- Herpes simplex
- Yellow fever
- Autoimmune hepatitis (female prevalence, chronic, indistinguishable from chronic
viral hepatitis)
- Drug/toxin-mediated injury mimicking hepatitis
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87. Liver cirrhosis - definition, classification, progression. Microscopic & gross

pathomorphology
The syllabus doesn’t have us talking about Hepatic failure specifically, but i want to cover it
here. The major clinical syndromes of liver disease are hepatic failure, cirrhosis, portal
hypertension and cholestasis. Hepatic failure is generally the end point of progressive liver
damage, either thanks to gradual or sudden destruction of hepatocytes, around 90% of
hepatic function should be lost before we call it hepatic failure. Patterns that cause
hepatic failure are:
- Acute liver failure with massive hepatic necrosis
- Chronic liver disease (most common route)
- Hepatic dysfunction without overt necrosis
Clinical features are jaundice, hypoalbuminemia, hyperammonemia, palmar erythema,

spider angiomas and hypogonadism and gynecomastia in men.
Right, now Cirrhosis.
Liver cirrhosis is a diffuse process characterized by fibrosis and conversion of normal

liver tissue into abnormal nodules, the main characteristics are:
- Fibrous septa - broad fibrous deposits around multiple adjacent lobules
- Parenchymal nodules - range in size
It is the end stage process of liver damage that may have multiple causes, the most common
being Hep B, C, alcoholic and nonalcoholic steatohepatitis.
Pathogenesis
- Three main processes, death of hepatocytes, ECM deposition and vascular
reorganisation
- Fibrosis is present in liver capsule, portal tracts and around central veins
- Major source of fibrosis is the perisinusoidal stellate cells which transform to
myofibroblasts and lay down collagen fibers
- These stellate cells themselves produce growth factors for more stellate cells
(transforming growth factor Beta)
- Vascular injuries also occur in cirrhosis, with inflammation and thrombosis of portal
veins, hepatic arteries and/or central veins, causing zones of parenchymal
hypoperfusion causing atrophy.
- We also see conversion of thin-walled sinusoids into higher pressure which increases
speed of fluid movement and inhibits protein movement.
Clinical feature are that of progressive liver failure, complication related to portal
hypertension and development of hepatocellular carcinoma.
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88. Portal hypertension - pathogenesis, vascular and organ-specific

manifestations, complications
Portal hypertension is increased resistant in the portal system, most commonly caused
by cirrhosis due to the fibrosis that occurs (see above for full pathogenesis of cirrhosis).
Less common causes include schistosomiasis, fatty changes and diffuse granulomatous
diseases.
In cirrhosis we see increased pressure at the level of the sinusoids due to perivenular
fibrosis and expanded) parenchymal nodules. This goes on to cause ascites (collection
of fluid in the peritoneal cavity, hepatomegaly (due to congestion of venous blood in the
liver), esophageal varices, caput medusae and hemorrhoids, as well as the symptoms
from normal liver cirrhosis.
As the portal pressure rises, portosystemic shunts develop, the principal sites are the
rectum (hemorrhoids) and the cardioesophageal junction (esophageal varices), as well
as the retroperitoneum and falciform ligament of the liver. These varices bleed easier
and appear in a high percentage of patients with cirrhosis.
Long standing portal hypertension also causes splenomegaly, as the splenic vein feeds into
the portal system, decreased flow through the portal system causes venous blood to build up
in the spleen. This can cause a variety of hematologic abnormalities.
89. Primal hepatic carcinoma - hepatocellular/cholangiocellular. Etiology &

pathogenesis. Secondary (metastatic) liver tumors. Microscopic & gross
pathomorphology; differences in diagnosis.
The main primary hepatic carcinoma is hepatocellular carcinoma. Let’s take a look.
Hepatocellular carcinomas are preceded by cellular changes and nodular lesions found
in chronic viral hepatitis, alcoholic liver disease and metabolic disease. It is often said
that cirrhosis itself is premalignant, however it takes years for this to become HCC. There
are two forms of cellular dysplasia, Large cell change and small cell change, these
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combined with dysplastic nodules mark the major pathways for hepatocellular
carcinomas.
HCCs are not uncommon, especially in regions with high Hep B incidence. There are
several factors relevant to its pathogenesis
- Major etiologic association with Hep B, C, alcoholic cirrhosis and toxin exposures
- In most cases HCC develops from small-cell high grade dysplastic nodules in
cirrhotic livers
- Tumours may arise from mature hepatocytes and progenitor cells
- A universal feature off HCC is the presence of structural and numerical chromosomal
abnormalities with genetic instability.
HCCs may appear unifocal, multifocal or diffusely infiltrative, it has a strong propensity
for vascular invasion, increasing the risk of metastases. On histological examination,
HCCs can show well differentiated lesions that produce hepatocytes arranged in
regular patterns or very poorly differentiated cell structure.
Secondary tumours
- Most common are metastatic carcinomas from the colon, lung and breast
- Metastatic cancers are more common than primary cancers
- Normal methods of metastasis
90. Acute and chronic cholecystitis, cholangitis/cholangiohepatitis. Liver abscess.

Etiology & pathogenesis. Microscopic & gross pathomorphology
Acute and chronic cholecystitis
Cholecystitis is inflammation of the gallbladder. It may be chronic, acute or acute
superimposed on chronic. It is almost always due to gallstones (see below).
In acute cholecystitis the gallbladder is enlarged, tense, bright red and often has
subserosal hemorrhage with a fibrinous cover (or fibrinopurulent in severe cases). 90%
of cases are due to blockage of the neck of the gallbladder or the cystic duct. The
gallbladder may be filled with cloudy bile that may contain fibrin, blood and pus, where
there is mostly pus this is empyema of the gallbladder. In the most severe cases the
gallbladder can become gangrenous.
In chronic cholecystitis morphological changes are highly variable, and often subtle.
Gallbladder may be contracted, enlarged or normal size, ulcerations are infrequent, but
mucosal wall is generally thickened from fibrosis.
The vast majority of acute cholecystitis is due to cholelithiasis. The stones block the duct
and cause chemical irritation, causing hydrolysis of biliary lecithin to lysolecithin, toxic
to the mucosa. Chronic cholecystitis is generally due to non-obstructive gallstones
that have irritated and damaged the inner mucosa. Additionally, chronic cholecystitis can
be due to bacterial infection (such as e.coli).
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Symptoms of the acute form are right subcostal pain and tenderness, the chronic form
has less pain and is generally recurrent attacks of epigastric pain, nausea, vomiting and
intolerance for fatty foods.
Cholangitis
This is inflammation of the bile duct. It is is generally found along with choledocholithiasis,
which is when stones are in the bile ducts. Stones in the bile duct may not cause full
obstruction, instead the symptoms can be liver abscess, chronic liver disease with
secondary biliary cirrhosis, cholecystitis, cholangitis or full biliary obstruction.
Cholangitis is just the term for acute inflammation of the bile ducts, the pathogenesis is
generally stones occur, causing slowing down of bile flow, which creates a home for
bacterial growth which causes the inflammation. Symptoms include fever, pain, chills and
jaundice.
Liver abscess
This is a pus-filled mass in the liver, commonly caused by abdominal infections such as
appendicitis or diverticulitis and spread hematogenously via the portal vein. The main
types are:
- Pyogenic liver abscess (often polymicrobial)
- Amoebic liver abscess
- Fungal abscess
Can also be caused by obstruction of the common bile duct (see above) causing bile slow
down, build up of bacteria and bacterial infection.
91. Cholelithiasis. Types of stones. Complications. Carcinoma of the gallbladder

and extrahepatic bile ducts
- Gallstones are broken down into two main types:

- Cholesterol gallstones (70-90%) - these are yellowish in colour, contain
undissolved cholesterol and are visible on X-ray due to the high amount of
calcium carbonate
- Pigment gallstones that can arise anywhere in the biliary tree (not just the
gallbladder) are are a browner colour thanks to the bilirubin the contain. They
also have glycoproteins and proteins. These are radiolucent.
- All gallstones are formed by one of the following:
- Too much cholesterol
- Too much bilirubin
- Inability of the gallbladder to empty
- Risk factors
- Forty +
- Female
- Fat
- Fertile (estrogen levels)
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- Complications
- Inflammation of gallbladder (cholecystitis)
- Inflammation of pancreas (pancreatitis)
- Inflammation of liver (hepatitis)
Carcinoma of the gallbladder

Carcinoma of the gallbladder is the most frequent malignant tumour of the biliary tract.
Higher prevalence in women, thought to be tied into prevalence of gallstones. Tumours
may be exophytic or infiltrating (more common) in growth, and appear as a area of diffuse
thickening of the gallbladder wall. Most are adenocarcinomas, a small percent are SCC.
Symptoms are vague, presents with jaundice, anorexia, abdominal pain and nausea.
We can also have cholangiocarcinomas (a type of adenocarcinoma) coming out of the

hepatobiliary tree.
92. Acute necrotizing pancreatitis, hemorrhagic pancreatitis. Chronic pancreatitis.

Etiology & pathogenesis. Microscopic & gross pathomorphology
Pancreatitis is inflammation of the pancreas, it can be acute or chronic.
The most common causes are gallstones and alcohol use, as well as trauma, infectious
agents and tumours.
Acute pancreatitis
- The exocrine part of the pancreas secretes digestive enzymes into the duodenum
that break down carbohydrates, lipids and proteins. As these are found in the
pancreas itself, the pancreas secretes inactive forms, which are then activated by
proteases in the duodenum.
- If these enzymes activate too early, they can cause acute pancreatitis. One such
example is the enzyme Trypsinogen.
- Etiology:
- Alcohol induced
- Alcohol increases trypsinogen secretion but decreases fluid and
bicarbonate in the pancreatic ducts. This thickens the pancreatic
juices, and makes them very viscous.
- The viscous pancreatic fluid can form a plug in the pancreatic duct,
causing backing up of the juices.
- This can cause the inactive Trypsinogen to fuse with lysosomes,
converting it to Trypsin and activating it.
- Trypsin, now active then begins autodigestion of the pancreas
- Gallstones
- Gallstones can get lodged in the sphincter of Oddi (where both the
common bile duct and pancreatic duct come together to excrete into
the duodenum). This blockage once again causes clogging of the
pancreatic duct and therefore a build up of pancreatic juices.
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- From here the pathogenesis is the same as the alcohol induced form.
- Other causes are Idiopathic, trauma (puncture), steroids, mumps autoimmune
disease, scorpion sting, hypercalcemia, endoscopic retrograde
cholangiopancreatography and drugs (I GET SMASHED). Additionally, Cystic
Fibrosis can cause acute pancreatitis, due to the fact it makes pancreatic
secretions thicker.
- Eventually, acute pancreatitis can lead to pancreatic tissue destruction, triggering an
inflammatory response, and liquefactive hemorrhagic necrosis.
- Clinical signs
- Nausea
- Vomiting
- Pain
- Hypocalcemia
- Bruising around belly button and flank
- Complications include pancreatic pseudocyst which itself can become an abscess,
rupture and others. Additionally, bleeding, disseminated intravascular coagulation
and acute respiratory distress syndrome can all occur.
The Pathomorphological changes in acute pancreatitis are:

- Microvascular leakage causing edema
- Necrosis of fat by lipases
- Acute inflammatory reaction
- Proteolytic destruction of pancreatic parenchyma
- Destruction of blood vessels leading to interstitial hemorrhage
The most severe forms of pancreatitis are acute necrotising pancreatitis, where necrosis
affects acinar and ductal tissues as well as islets of langerhans. Macroscopic appearances is
red-black hemorrhagic areas with areas of chalkly necrosis. Fat necrosis can also occur,
which can go on to become hemorrhagic pancreatitis, extensive parenchymal necrosis is
seen with diffuse hemorrhage.
Chronic Pancreatitis
- Often due to repeated bouts of acute pancreatitis
- This is inflammation of the pancreas caused by irreversible tissue changes such as
fibrosis, atrophy and calcification of the tissue.
- With recurrent bouts of acute pancreatitis we see ductal dilation and acinar cell
atrophy. The body lays down fibrotic tissue, which in the long term narrows the
ducts.
- This process of laying down fibrotic and calcified tissues is the process of chronic
pancreatitis.
- Diagnosis is generally via imaging (endoscopy, X-rays or CT-scan).
- Chronic calcification can lead to pancreatic insufficiency (see below).
- Complications include
- Diabetes mellitus
- Pseudocyst formation
- Pancreatic cancer
- Treatment is pain management and risk factor control.
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93. Tumors of exocrine and endocrine pancreas
The pancreas can have cystic or solid neoplasia, but not all cysts are neoplastic! Only 5-15%
are. Let's take a look at some of our cysts!
Serous Cystadenomas account for 25% of cystic neoplasms, they are composed of
glycogen rich cuboidal cells within which sits fluid. These are entirely benign, and surgical
resection is curative.
Mucinous cystic neoplasms are almost exclusively female and arise in body or tail of
pancreas. The cystic spaces are filled with thick, tenacious muchsin and the cysts are lined
with columnar epithelium. Mucinous cystic neoplasms can be defined as low-grade,
moderate or severely dysplastic based on cytological examination of epithelial lining.
Intraductal papillary mucinous neoplasms are mucin producing intraductal neoplasms,

occurring more frequently in men. They arise in the pancreatic duct, and show various
grades of dysplasia with invasive adenocarcinoma components.
And now, onto the solids! There's only one we really care about here, and that’s infiltrating
ductal adenocarcinoma of the pancreas, commonly called pancreatic cancer. High death
rate, arises due to inherited and environmental conditions. KRAS oncogene is most
frequently altered (impairing GTPase of Kras protein) along with p16 inactivation (a tumour
suppressor). The majority of these adenocarcinomas arise in the head (60%) and body
(15%). They appear as hard, grey-white, poorly defined masses. It is a highly invasive
cancer and causes a strong non-neoplastic host reaction (desmoplastic response). They
generally obstruct the common bile duct when found in the head, and this gives first
symptoms, if in the tale, it is generally very late before they are identified. Differentiation of
the cells is generally poor and dense stromal fibrosis can be seen along with lymphatic
invasion.
Renal Pathology
94. Primal glomerular diseases - glomerulonephritis. Etiology & pathogenesis.
Classification. Microscopic & gross pathomorphology.
Glomerulonephritis is a condition of kidneys diseases characterised by injury to the

glomeruli or of small blood vessels in the kidney. There are different types of injury to
the glomeruli which in one or both of the nephrotic or nephritic syndromes.
Nephrotic syndrome is characterised by edema in a person with increased protein in

urine and decreased protein in blood, along with increased fat in blood (due to
increased production of lipoprotein and increased lipid catabolism). Glomeruli are affected
by inflammation (or hyalinization) that allows proteins such as albumin or
immunoglobulins to pass through the cell membrane and appear in the urine. As a response
the liver compensates with increased protein production. The loss of proteins in urine
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accounts for edema, while the increased protein production accounts for lipoproteins
in the blood. Causes can be primary or secondary:
- Primary glomerulonephritis (intrinsic to the kidney)
- Minimal change disease (common in children)
- Histology - appears normal under light microscope. Cells of proximal
tubule often have protein droplets and lipids. Only obvious change is
uniform and diffuse effacement of foot processes of podocytes
- Focal segmental glomerulosclerosis (common in adults, scaring in glomeruli)
- Histology - Affects only some glomeruli (hence focal), those affected
show increased mesangial matrix, loss of capillary lumina, hyalinosis
and lipid droplets
- Membranous glomerulonephritis (inflammation of glomerular membrane,
autoimmune)
- Histology - diffuse thickening of capillary wall with effacement of foot
processes and granular deposits
- Membranoproliferative glomerulonephritis (deposition of antibodies in
glomeruli membranes along with inflammation)
- Histology - larger glomeruli, proliferation of mesangial and endothelial
cells with thick basement membrane.
- Rapidly progressive glomerulonephritis
- Secondary glomerulonephritis (associated with non-kidney factors)
- Diabetic nephropathy
- Systemic lupus erythematosus
- Sarcoidosis
- Syphilis
- Hepatitis B
Nephritic syndrome is characterised by blood in the urine and a decrease in urine along
with presence of hypertension. This syndrome sees inflammatory damage to cells
lining the glomerulus which destroy the epithelial barrier which usually keeps RBCs in.
It may present with hematuria, proteinuria or as a nephrotic syndrome, nephritic

syndrome, acute or chronic renal failure.
Causes of nephritic syndrome include:

- IgA nephropathy, post-streptococcal glomerulonephritis, hemolytic uremic syndrome
and Henoch-Schonlein purpura in children
- Histology - increased cellularity of glomerular tufts with subepithelial humps
against basement membrane and granular deposits of IgG and complement
with the capillary walls
- Goodpasture syndrome, systemic lupus, rapidly progressive glomerulonephritis and
infective endocarditis in adults.
The pathophysiology of both Nephrotic and Nephritic syndromes is generally dependent on

damage done by antibody-antigen complexes in the glomeruli, which in turn cause an
inflammatory response and finally result in glomerular scarring. The location of complex
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deposition, and by extension the damaged caused, will determine if the syndrome presents
as nephrotic or nephritic.
At the most basic level, remember, Nephrotic syndrome is loss of proteins, while
Nephritic syndrome is loss of blood, both are caused by damage to the glomeruli,
commonly by autoimmune complexes.
Glomerulonephritis can also be divided into nonproliferative and proliferative conditions,

these are divided as so:
- Nonproliferative (mostly nephrotic) (number of cells not changed)
- Minimal change disease
- Focal segmental glomerulosclerosis (sclerosis of some segments of
glomerulus)
- Membranous glomerulonephritis (thickened basement membrane without
hyperproliferation of glomerular cells)
- Thin basement membrane disease (genetic, AD)
- Proliferative (mostly nephritic) (increased number of cells in glomerulus)
- IgA nephropathy
- Post-infectious (circulating immune complexes deposit in glomerulus)
- Membranoproliferative (may be secondary to lupus, hep B or C)
- Rapidly progressive glomerulonephritis (may be secondary to lupus,
goodpasture syndrome and others)
95. Inflammatory tubulointerstitial renal diseases - acute and chronic

pyelonephritis
Tubulointerstitial nephritis is a group of inflammatory diseases that affect the interstitium

and and tubules, while the glomeruli may be spared or affected late in the show. Most
cases TIN is as a result of bacterial infection and the renal pelvis predominantly involved,
as such we call it pyelonephritis, while the term interstitial nephritis usually reserved for
infections that are of non-bacterial origin (including hypokalemia, radiation, viral infection
and immune reactions).
Acute pyelonephritis
A common suppurative inflammation of the kidney and renal pelvis of bacterial etiology,
commonly a complication of UTIs. Main etiology are E.coli, Proteus, Klebsiella,
Enterobacter and Pseudomonas. Often the result of recurrent UTIs where bacteria
ascend up the ureters or travel via the bloodstream (ascending infection the most
common). Females are more susceptible due to their shorter urethras, and risk factors are
things that decrease bladder voiding (e.g. prostatic hyperplasia). Incompetence of the
vesicoureteral orifice can cause vesicoureteral reflux (VUR) which increases risks, this is
found in 20-40% of children who get UTIs.
Once the infection reaches the kidneys, we have a problem. The infection can be bi or
unilateral, and often makes the kidneys enlarged with yellowish raised abscesses that
appear on the renal surface. Histologically we see liquefactive necrosis with formation of
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abscesses in the renal parenchyma. Large masses of neutrophils (pus) enter the
collecting ducts and can even spread to the renal pelvis, calyces and ureter. A rare
complication is that of papillary necrosis of the renal papillae.
Clinical symptoms prevent with pain of the costovertebral angle and systemic evidence of
infection (chills, fever, malaise etc), often with turgid urine.
Chronic pyelonephritis
Chronic pyelonephritis is really a morphologic classification, where we see interstitial
inflammation and scarring in the renal parenchyma associated with scarring of the
pelvicalyceal system, it is a common form of chronic renal failure. It has two types:
- Chronic obstructive pyelonephritis
- Leads to recurrent bouts of inflammation and
- Chronic reflux-associated pyelonephritis
- More common form, resulting renal damage may cause scarring and atrophy
of one or both of the kidneys
The uneven scaring helps differentiate chronic pyelonephritis from systemic disease such
as benign nephrosclerosis. The hallmark of chronic pyelonephritis is scarring of pelvis or
calyces or both, leading to calyceal deformities. Microscopic changes are nonspecific.
We will see fibrosis and inflammatory infiltrates of lymphocytes and plasma cells, dilation of
tubules, arteriosclerosis and glomerulosclerosis.
A quick note on Acute Tubular injury

- This is a clinicopathologic definition characterised by damaged tubular epithelial
cells and acute decline of renal function with granular casts and tubular cells in
the urine.
- ATI can be caused by ischemic and nephrotoxic causes
96. Urolithiasis. Etiology & pathogenesis. Types of stones. Clinico-morphological

characteristics. Complications
Urolithiasis is calculus formation within the urinary tract, most commonly in the kidney.
There are three main types of stones:
- 80% are calcium oxalate (with or without calcium phosphate)
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- 10% are magnesium ammonium phosphate

- 6% are uric acid/cystine stones
The most important cause of urolithiasis is increased urinary concentration of the stone’s
constituents so it exceeds solubility, i.e. patients with calcium stones have hypercalcemia,
uric acid stones have hyperuricemia. Other causes include changes in urine pH and
bacterial infection.
Stones are generally unilateral and form in renal pelvis and calyces, often with many
stones in one calyces. Clinical presentation is with or without the intense pain known as
renal colic (characteristic pain of the flank that radiates towards groin) there may be
hematuria as well.
The main complication is urinary flow obstruction that causes hydronephrosis, that is to
say dilation of the renal pelvis due to a buildup of fluid. There are two categories:
- Congenital - due to atresia of the urethra, valve formations or other malformations
that may cause build up
- Acquired - FBs, proliferative lesions, inflammatory, neurogenic or normal pregnancy
Hydronephrosis can lead to kidney failure as we have a buildup of fluid pressure that
prevents glomerular filtration.
97. Inflammatory diseases of the urinary bladder (cystitis). Pathomorphological

classification. Tumors of the kidney and urinary tract.
Cystitis
Cystitis is the inflammation of of the urinary bladder, common symptoms include dysuria,
frequency and urgency, it may or may not be associated with infection of the urethra.
Common etiology is bacterial, thanks to E.coli, Proteus, Klebsiella and enterobacter
which ascend through the urethral opening. Alternatively, Cystitis cystica and cystitis
glandularis are reversible alterations to the urothelial which cause irritation, eosinophilic
cystitis (autoimmune), follicular cystitis (background of chronic cysts), Hemorrhagic cystitis
(common side effect of radiation).
Gross findings are nonspecific, but edema, hyperemia, petechiae and ulceration may all
be evident. Histologically, edema and/or chronic inflammatory infiltrate of the lamina
propria are present, although it's worth mentioning that tissue sampling in acute stage of
disease is contraindicated. In disorders such as cystitis cystica and cystitis glandularis we
see cystic spaces develop, lined with columnar epithelium which may also have a ring of
transitional epithelium. More valuable than tissue sampling is urine analysis to observe
bacteria in the urine.
Tumours
Most common benign tumour is cortical papillary adenoma, found in 40% of all adults and
have no clinical significance.
Most common malignant tumour is renal cell carcinoma, followed by nephroblastoma

(Wilms tumour).
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Renal cell carcinoma

- Derived from renal tubular epithelium, mostly in the cortex
- 40% mortality rate, men more at risk, polycystic ovary disease increases risk 30x
- Classification based on growth pattern:
- Clear cell carcinoma - composed of cells with clear cytoplasm, solitary and
large. Gross appearance is yellow to white with areas of cystic softening and
hemorrhage. Tumour commonly invades renal vein
- Papillary Renal Cell carcinoma - rarer, show papillary growth pattern,
frequently multifocal and bilateral
Haematologic & Bone Marrow Diseases

98. Primal diseases of bone marrow - hemolytic and iron deficiency anemias.
Etiology, pathogenesis & pathomorphological characteristics of target organs.
Anemia is a deficiency of RBCs or haemoglobin in the blood. There are different causes
(hemorrhagic, hemolysis, decreased RBC production (iron def)) ,and different
morphologies (microcytic, macrocytic, normocytic).
Hemolytic anemias are due to premature destruction of RBCs prior to their normal lifespan of
120 days. Destruction can be due to an intrinsic RBC defect, or extrinsic factor.
- Intrinsic hemolytic anemias
- Membrane abnormalities (e.g. spherocytosis)
- Enzyme defects (e.g. glucose 6 phosphate dehydrogenase)
- Disorders of hemoglobin synthesis (e.g. sickle cell anemia)
- Extrinsic hemolytic anemias
- Transfusion reactions
- Autoantibodies (idiopathic, drug associated)
- Mechanical trauma (e.g. defective cardiac valves)
- Infections (e.g. malaria)
Below we will take a look at some examples of hemolytic anemias:

- Hereditary spherocytosis
- AD mutation to membrane skeleton, causes change of RBC shape
- Spherical RBCs are unable to properly pass through splenic cords and are
hemolyzed within the spleen
- Treatment isn splenectomy - splenomegaly is very common
- Sickle cell anemia
- Most common hemoglobinopathy from Beta-globin gene mutation
- Mutation causes RBC to become sickled when deoxygenated
- Over time RBCs irreversible sickle causing them to be hemolyzed
- Results in chronic hemolytic anemia and microvascular obstruction and
moderate splenomegaly
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- Thalassemia
- Mutation to alpha or beta globin chains, common in mediterranean, african
and asian regions
- beta-Thalassemia (minor or major) - reduced HbA formation, causing
hypochromic and microcytic RBCs, with imbalance of beta and alpha globin
chain synthesis, which causes damage to the RBC membranes leading to
increased RBC hemolysis and iron overload
- alpha-Thalassemia - depending on number of genes can be asymptomatic,
severe (similar symptoms to beta thalassemia), or lethal in utero
- In both cases cells are microcytic and hypochromic
- Glucose-6-Phosphate Dehydrogenase Deficiency
- RBCs don’t have G6PD gene and are therefore vulnerable to oxidative injury
that causes haemolysis. X-linked disease
- Asymptomatic until exposure to environmental factor that produces oxidants
(e.g. drugs)
- Paroxysmal nocturnal hemoglobinuria
- Hemolytic anemia that occurs due to acquired somatic mutation in myeloid
stem cells
- PIGA gene mutation, causes RBC precursors to be too sensitive to
complement-mediated lysis.
- X-linked
- Malaria
Iron deficiency anemia

- Most frequent cause of anemia
- Iron is transported through epithelial cells by being pound to transferrin, deficiency of
transferrin means iron cannot be absorbed
- Iron balance is maintained by regulating absorption of dietary iron in the duodenum
- Iron deficiency anemia can come due to chronic blood loss (e.g. peptic ulcer, colonic
cancer, hemorrhoids), due to low iron intake, or due to malabsorption (e.g. with
celiac)
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- RBCs are hypochromic and microcytic, clinical symptoms are tiredness, palor,
fingernail abnormalities, and the weird tendency to want to eat dirt!
99. Primal diseases of bone marrow - megaloblastic and pernicious anemias.

Etiology, pathogenesis & pathomorphological characteristics of target organs.
Megaloblastic anemias simply mean that the bone marrow is hypercellular with larger
than normal erythroid progenitors. There are two principal mechanisms: folate
deficiency and B12 deficiency. Both vitamins are required for D NA synthesis, reduced
amounts mens we can produce fewer RBCs, and the body tries to pack as much
haemoglobin as it can into the RBCs it does produce. In the peripheral blood the earliest
changes are appearance of hypersegmented neutrophils (appear before fully fledged
anemia). Let's now look at the two types of megaloblastic anemia:
- Folate (folic acid) deficiency
- Not common, risk in those with poor diet, present in all foods but destroyed
with cooking
- Absorbed in proximal ⅓ of intestines
- Clinical onset is gradual with nonspecific symptoms include weakness,
fatigability etc. Unlike B12 anemia (below) there are no neurological
symptoms
- Vitamin B12 (pernicious anemia) deficiency
- Low B12 (cobalamin) results in a morphologically identical anemia to folate
deficiency
- Many causes, but the lack of intrinsic factor (which absorbs B12) is key
- Technically pernicious anemia is an autoimmune condition
against parietal cells and intrinsic factor, the loss of intrinsic factor
means B12 cannot be absorbed. However, as this is by far the most
common cause of B12 deficiency, the terms are often used
interchangeably.
- Main clinical symptoms beyond anemia are demyelination of posterior and
lateral columns of the spinal cord, causing possibly severe neurologic deficits
100. Acute and chronic leukemia. Pathomorphology of target organs: bone

marrow, spleen, liver, lymph nodes
Leukemia is a group of cancers, originating in the bone marrow, that cause high numbers
of (immature) white blood cells.
First, we need to remember, what are myeloid and lymphoid cells, and more specifically,
what are myeloblasts and lymphoblasts?
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Right, types of leukemia

- We can divide based on the lineage affected:
- Myeloid
- Lymphoid
- And based on onset
- Chronic
- Acute
First, let’s take an overall look at the four main types of leukemia.
Acute lymphoblastic leukemia

- Overproduction of immature white blood cells (lymphoblasts). This
overproduction occurs in the bone marrow, and sees a reduction in lymphoblast
quality
- Most common occurrence in childhood 2-5 years of age
- Symptoms include increased risk of bacterial infection, dyspnea, chest pain,
tendency to bleeding and general anemic symptoms
- Thought to be a cancerous gene affecting the lymphoblast
- Can be further subcategories based on if it affects T- or B-lymphocytes more
- T-ALL goes on to cause thymic mass (Thymoma), more common in
teenagers
- Most common blood neoplasm in children
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Chronic lymphoblastic leukemia

- Most common type of leukemia affecting adults
- B-cells grow in uncontrolled manner and accumulate in bone marrow where they
crowd out healthy blood cells
- Results in swollen lymph nodes, spleen and liver, eventually with anemia and
infections. Eventually, these develops into lymphomas (masses in the lymph nodes)
Acute Myeloid leukemia

- Cancer of myeloid line with rapid growth of cells that build up in bone marrow and
effect other normal cell production
- Rare, treated with bone marrow replacement therapy, more common in older
adults
- One important subtype is acute promyelocytic leukemia (t(15;17)), these increase
risk of DIC
- Can also categorise based on cell, monoblast AML or Megakaryoblast AML
- Symptoms include infections, anemia, and frequent bleeding
Chronic Myeloid leukemia

- Gradual proliferation of myeloid cells in bone marrow
- Linked with genetic abnormality known as Philadelphia chromosome (t9;22,
BCR-ABL)
- Causes myeloid cells to divide beyond what they should normally, creating many
myeloblasts
- Causes hepato and splenomegaly
- Most common blood neoplasm in adults
- Has a Chronic and Accelerated phase
In acute leukemias, peripheral blood smears show a high prevalence of lymphoblast

cells, these are larger than normoblast cells and lower in cytoplasm than their
contemporaries. Myeloblast and Lymphoblast cells look identical under microscope, and
chemical markers must be used to distinguish between the two.
- Lymphoblasts have TdT+ nuclear staining
- Myeloblasts have myeloperoxidase enzyme (cytoplasmic staining/observation
of auer rod)
In chronic leukemias, the cells are partially matured, more mature than acute form however.
In CML, cells divide too quickly, in CLL cells don’t die as they should.
In both acute and chronic forms we have this ‘crowding out’ of normal cellular development
in the bone marrow. This means reduced RBCs (anemia and fatigue), thrombocytopenia
(increased bleeding) and leukopenia (reduced white blood cells and so more infections).
101. Non-Hodgkin's lymphoma and Hodgkin’s disease - basic histologic types.

Target organs
What is a lymphoma? A lymphoma is simply tumour cells in lymph nodes as a localised
mass that can progress into leukemia.
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There are two main classes of lymphoma:

- Hodgkin's lymphomas
- Distinctive neoplastic Reed-Sternberg giant cells
- Generally affect axial lymph nodes (cervical, mediastinal, para-aortic)
- Histological types, based on cellular morphology and cell infiltration in lymph
node biopsy:
- Classical
- Nodular sclerosing
- Lacunar cells
- Mixed-cellularity subtype
- Lymphocyte rich
- Lymphocyte depleted
- Nodular lymphocyte-predominant
- Symptoms include swelling of lymph nodes, fatigue, fever, sweats and weight
loss
- Spread in in a stepwise fashion along lymph chains
- Two peaks of incidence, adolescence and >50 y.o.
- Non-Hodgkin's lymphoma
- Can start in almost any part of the body (unlike Hodgkin's which starts in a
single node)
- Generally onset is older (over 65)
- Many subtypes but generally
- Aggressive
- Indolent (slow development)
Hodgkin Lymphoma Non-Hodgkin Lymphoma
Localised to single group of nodes Frequent involvement of multiple nodes
Orderly stepwise spread Non orderly spread
Mesenteric nodes and Waldeyer's ring Mesenteric nodes and waldeyer's ring
rarely involved commonly involved
Extranodal involvement uncommon Extranodal involvement common
All types of lymphoma have four clinical stages:

- Stage I - involvement of a single lymph node region
- Stage II - involvement of two or more lymph node regions
- Stage III - involvement of lymph node regions on both sides of diaphragm
- Stage IV - disseminated involvement of one or more extralymphatic organs
102. Lymphadenitis. Types of lymphadenitis according to histological

characteristics
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Lymphadenitis is inflammation of the lymph nodes, it is a type of lymphadenopathy.

Lymphadenitis occurs thanks to exposure to bacteria, viruses or fungi, causing swelling of
the lymph node. Symptoms may include redness, swelling, tenderness of node, or solidity of
the node. They can feel rubbery if an abscess has formed.
There are two main types:

- Localised lymphadenitis
- Generalised lymphadenitis (2+)
Can also be described based on onset:
- Acute
- Chronic
Macroscopically, all nodes just appear enlarged, chronic form may have thickened
capsule, acute form may have suppuration leading to necrosis and abscess.
Microscopically, acute form shows sinus dilation, accumulation of neutrophils, vascular
dilation and edema, if bacterial with suppurative inflammation and necrotizing
inflammation in bubonic plague. Microscopically in chronic form, observe follicular
hyperplasia, increased immunoblasts, plasma cells and presence of fibrosis.
Diseases of reproductive systems
103. Benign prostatic hyperplasia. Prostatic carcinoma

Benign prostatic hyperplasia
The prostate is a walnut sized gland between the bladder and the penis. The urethra runs
through the center of the prostate from the bladder to the penis letting urine out. Benign
prostatic hyperplasia (nodular hyperplasia) is extremely common in elderly men (90%) and
is characterized by proliferation of stromal and epithelial cells with enlargement of the
gland and commonly urinary obstruction. It is related to excessive androgen-dependent
growth, Dihydrotestosterone (DHT) is the ultimate mediator for prostatic growth.
The hyperplasia always occurs in the inner transitional zone of the prostate, and contains
many well circumscribed nodules that bulge from the surface. This commonly compresses
the urethra and gives our main clinical symptom of lower urinary tract obstruction (hesitancy,
frequency, urgency, nocturia etc).
Prostatic carcinoma
This is a common adenocarcinoma of men aged 65-75. Androgens are central to the
cancers development, as the cancer will develop in response to androgens (hormone
dependent). Hereditary, environment and acquired genetic mutations all also play a role.
Most carcinomas are not visible grossly, more advanced lesions are firm, gray-white
lesions with poorly defined margins. Histology shows loosely differentiated
adenocarcinoma that produce well defined glands. With increasing grade we see
increased irregularity. Prostatic adenocarcinomas are given a Gleason score to grade them
into grades I - IV, I is the most well differentiated tumours while grade 5 have no glandular
differentiation.
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Prostatic carcinomas can be identified on routine screening and observation of increased

prostate-specific antigen (PSA).
104. Inflammatory diseases of the testis. Testicular tumors - types according to

histological classification and origin
Inflammatory diseases of the testis

Inflammatory lesions of the testis are more common in the epididymis than in the testis
proper. Orchitis is the term given to inflammation of the testis, it involves swelling, pain,
hematospermia, hematuria and often involves the epididymis.
Causes can be due to STDs such as chlamydia and gonorrhea, and as a result of mumps.
Ischemic orchitis may result from damage to the blood vessels of the spermatic cord during
inguinal hernia and can lead to testicular atrophy. Common bacteria, infections are E.coli,
Staph and Strep.
When untreated, orchitis can lead to infertility, loss of the testis, and death!
Testicular tumours
Testicular tumours are the most common cause of painless testicular enlargement, and
occur with greater incidence in those with undescended testis and testicular dysgenesis.
Incidence is 6/100,000, 95% arise from germ cells and are all malignant, while the 5% that
arise from Sertoli or Leydig cells are usually benign. Below we consider some of the germ
cell tumours:
- Seminoa - peak incidence 40-50 y.o., sheets of uniform polygonal cells with clear
cytoplasm and lymphocytes in stroma
- Embryonal carcinoma - peak incidence 20-30 yr, poorly differentiated, pleomorphic
cells in cords, sheets, papillary formation containing some yolk sac and
choriocarcinoma cells
- Yolk sac tumour - 3 yrs, poorly differentiated endothelial like cuboidal/columnar cells
- Choriocarcinoma - Cytotrophoblast and syncytiotrophoblast without villus
- Teratoma - tissues from all three germ layers with various differentiation levels
- Mixed tumour - commonly teratoma and embryonal carcinoma
105. Uterine body carcinoma. Etiology & pathogenesis. Precancer. Histological

classification.
Endometrial carcinoma is the most frequent cancer of the female genital tract, commonly
appearing ages 55-65. There are two types:
- Endometrioid
- Serous carcinoma
These are histologically and pathologically distinct. Endometrioid cancers arise in
association with estrogen excess and endometrial hyperplasia in perimenopausal
women, while serous carcinomas arise thanks to endometrial atrophy in
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postmenopausal women. Endometrial hyperplasia can be simple without atipia, or

complex hyperplasia.
Endometrioid cancer
- The majority of endometrial carcinomas - endometrial hyperplasia is an important
precursor lesion
- Histologically similar to normal endometrial glands, risk factors are:
- Obesity
- Diabetes
- Hypertension
- Infertility
- Exposure to unopposed estrogen
- Breast carcinoma often occurs along with endometrioid carcinoma
- Mutation to PTEN gene common, along with PTEN mutation (TP53 less common)
- Histologically, closely resembles normal endometrium, may be infiltrative or
exophytic, structure may be mucinous, tubal and/or squamous. Commonly
metastasise to regional lymph nodes
Serous endometrial carcinoma

- Less common, 15%
- Nearly all have TP53 mutation whereas PTEN mutation is rare
- Forms small tufts and papillae rather than glands seen in endometrial form
- Behave aggressively and are by definition high-grade
106. Precancer of the uterine cervix. Cervical intraepithelial neoplasia (CIN).

Importance of early diagnostic methods - cytology, histology.
Most cervical lesions are harmless inflammations, but cervical carcinoma is also one of the
most common forms of cancer.
Most cervical cancers are epithelial i n origin and caused by oncogenic strains of human
papillomavirus (HPV). HPV is selective for immature squamous cell of the
transformation zone, where squamous epithelial cells and mucus secreting epithelial cells
both exist.
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Most HPV infections are eradicated quickly without issue, however, some form a precursor
lesion. The infection occurs at the most immature squamous cells at the basement
membrane, however HPV DNA replication occurs in the overlying squamous cells
thanks to expression of two oncoproteins, E6 and E7 that promote growth. Different
infections can be high or low risk for development of Cervical Intraepithelial Neoplasia
(CIN), HPV 16 and 18 account for 70% of cases.
CIN is HPV related carcinogenesis changes, which have three categories:

- CIN I - low grade dysplasia
- Found in lower third of squamous epithelium and koilocytotic change in
superficial layers
- CIN II - moderate dysplasia
- Dysplasia extends upwards, affecting bottom ⅔ now, takes form of delayed
keratinocyte maturation
- CIN III - severe dysplasia
- Marked by complete cell atypia
This dysplasia can be observed on smeres, and early detection of the dysplasia allows us to
catch cervical cancer early. Recently a vaccine has been introduced for HPV which is highly
effective. CIN is asymptomatic and only comes to attention through a smear test.
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107. Carcinoma of the uterine cervix. Etiology, pathogenesis, types, microscopic

& gross pathomorphology
Most common cervical carcinomas are squamous cell carcinomas, followed by

adenocarcinomas and mixed adenosquamous carcinomas. All are caused by HPV.
Peak incidence about 45 years, about a decade after peak incidence of CIN. Risk factors
include smoking and HIV.
Invasive carcinomas develop in the transformation zone of the cervix, and can undergo
microscopic invasion or gross exophytic growth. Tumours encircle the cervix and
penetrate the stroma below to form a barrel cervix. There is a high chance of lymph
metastasis.
CIN III dysplasia is the precancerous lesion (see above for full pathogenesis) and should
be observed on smear tests.
108. Ovarian epithelial tumors - benign & malignant. Germ cell and sex
cord-stromal tumors. Classification.
Ovarian cancers are the 8th most common cancer in the developed world. There is a wide
variety of cancers due to the presence of three cell types, multipotent surface epithelium,
totipotent germ cells and sex cord-stromal cells, each of which give rise to different
tumours. Let's take a look:
- Surface epithelial tumours
- Accounts for the vast majority of malignant ovarian tumours
- We have classifed these below:
- Serous tumours
- Benign or malignant (25% malignant e.g. serous
cystadenocarcinoma)
- Include cystic and/or fibrous areas
- Lined by tall, columnar, ciliated epithelia, filled with serous
fluid, involve surface of ovary
- Mucinous tumours
- Less likely to be bilateral that serous form, less common
- Characterised by more cysts of variable size
- Lined with tall columnar epithelial cells, no cilia
- Endometrioid tumours
- 20% of all ovarian cancers, mostly malignant (endometrioid
carcinoma)
- Made of tubular glands
- Clear cell tumors
- Large epithelial cells with clear cytoplasm
- Seen in association with endometriomas or endometrioid
carcinoma of ovary
- Brenner tumor
- Small cell tumors
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- Germ cell tumours

- Account for 15-20% of all tumours, 5% of malignant
- Categories are based on histology, germinomatous tumours lack any form of
histologic differentiation, while nongerminomatous germ cells display various
differentiations:
- Germinomatous
- Germinoma (malignant)
- Dysgerminoma
- Seminoma
- Nongerminomatous
- Embryonal carcinoma
- Endodermal sinus tumor (yolk sac tumour)
- Choriocarcinoma
- Teratoma
- Mixed
- Sex Cord-Stromal
- Tumours derived from stromal component of ovaries (and testis), composed
of granulosa, thecal cells and fibrocytes (basically, these are mesenchymal
tumours)
- They come from Sex Cord, (in women these are the follicles), Gonadal
stromal or can be mixed.
- The tumours are:
- In women: Granulosa cell tumour, Thecoma fibroma and
sertoli-leydig cell tumour
- In men: sertoli cell tumour, leydig cell tumour and sertoli-leydig
cell tumour
109. Fibrocystic breast disease. Benign tumors: epithelial and mixed
So, lumps in breasts! Not good news, the good news, is only 10% of all patients coming in
with breast lumps have cancer, 40% meanwhile are fibrocystic changes, with another 20%
being benign neoplasia (msic benign and fibroadenoma), 30% are no lumps at all.
First, histology reminder, breasts are made of lobules (milk producing glands) and ducts
(that carry the milk to the nipple). These are surrounded by glandular, fibrous and fatty
tissues.
The term fibrocystic breast disease designates the pathological process of cyst formation
and fibrosis, they are likely a result of breast changes that occur in the normal
menstrual cycle. They can be subdivided as below:
- Nonproliferative changes
- Cysts and fibrosis - the most common type of fibrocystic lesions, there is an
increase in fibrous stroma along with dilation of ducts and formation of cysts
- Secretions in the cysts can calcify, producing microcalcifications on
mammograms.
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- Frequency the fibrotic cysts have large polygonal cells lining them, in a setting
known as apocrine metaplasia
- Proliferative changes
- Epithelial hyperplasia - increased epithelial cells in the lumen of the ducts
and lobules of the breast.
- Fenestrations and ductal papillomatosis can be observed
Features of fibrocystic changes can help us determine if there is an increased risk of cancer:
- Minimal/no increase in risk where there is fibrosis, cystic changes, apocrine
metaplasia
- Slightly increased risk where there is moderate hyperplasia or ductal
papillomatosis
- There is significantly increased risk where there is atypical hyperplasia
The most common benign breast tumour is a fibroadenoma, it can develop in puberty and
is a mixture of stromal and epithelial tissues, they develop from the lobules (milk
producing glands) and form a solid fibrous lump.
110. Breast carcinoma. Etiology, pathogenesis, clinic-morphological types and

histological variants
1 in 8 women will get breast cancer, there are three etiological areas:
1. Genetic changes
a. Overexpression of HER2/NEU
b. Amplification of RAS and MYC
c. With ⅓ of women having BRCA1 and BRCA2 mutations
2. Hormonal influences
a. Endogenous estrogen hormone imbalance post menopause is a a major RF
3. Environmental variables
Classifications
- Noninvasive
- Ductal carcinoma in situ (DCIS)
- Lobular carcinoma in situ (LCIS)
- Invasive (infiltrative)
- Invasive ductal carcinoma (most common type)
- Invasive lobular carcinoma
- Medullary carcinoma
- Colloid carcinoma
- Tubular carcinoma
- Others
Non Invasive carcinomas

- Both DCIS and LCIS arise from terminal duct lobular unit, DCIS fills and distorts
ducts, LCIS expands but does not alter acini of lobules, both are confined by
basement membrane and don’t invade
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- DCIS has solid, comedo, cribriform, papillary and micropapillary types. Necrosis can
also occur. Calcifications are frequently seen also, excellent prognosis.
- Paget disease of nipple is caused by extension of DCIS up lactiferous ducts
and into the contiguous skin of the nipple, producing crusting exudate
- LCIS has uniform appearance, monomorphic cells with round nuclei in cohesive
clusters. Rarely calcify and unlikely to be detected, LCIS can be a precoursor to more
dangerous other cancers.
Invasive carcinoma
- Invasive ductal carcinoma
- Majority of cancers, usually associated with DCIS (LCIS less commonly)
- Causes desmoplastic response causing breast fat to become fibrotic and hard
- Microscopic appearance is heterogenous, invasion of lymphovascular spaces
can be seen, ⅔ express estrogen or progesterone receptors
- Invasive lobular carcinoma
- Consists of identical cell morphology to LCIS, ⅔ associated with LCIS
- Cells invade single file into stroma, correlates with mutation of E-cadherin
protein
- May be diffusely invasive or single mass
- Frequently metastasis to CSF, serosal surfaces, GI tract, ovaries and bone
- Inflammatory carcinoma
- Defined by clinical presentation of swollen, red breast, without palpable mass
- Low survival rate
111. Toxemia of pregnancy. Pathomorphological characteristics of organ-site

damage
Toxemia of pregnancy, also known as the far more common Preeclampsia/eclampsia is

the development of hypertension with proteinuria and edema in the 3rd trimester, it
occurs in up to 5% of pregnant women. The term toxemia of pregnancy is a historic
misnomer, there are no toxins involved. Exact etiology is unknown, but the underlying
pathogenesis is insufficient maternal blood flow to the placenta, as a result of
inadequate remodeling of spinal arteries. The decreased uteroplacental blood flow results in
placental hypoxia, this leads to release of various antiangiogenic factors as well as
proangiogenic factors, the consequences of which are as follows:
- Placental infarction due to chronic hypoperfusion
- Hypertension due to reduced endothelial production of vasodilators
- Hypercoagulability due to endothelial dysfunction
- End organ failure (notably kidney and liver) which occurs in full blown state
Morphologically, we can see placental abnormalities:

- Infarcts
- Retroplacental hemorrhage
- Premature maturation of placental villi
- Fibrinoid necrosis
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Prompt therapy early in the course aborts the associated changes with all abnormalities
resolving after delivery.
112. Postpartum uterine infection. Postpartum sepsis. Pathomorphological

characteristics of organ-site damage
Postpartum uterine infection

- Infections that develop after delivery of baby in uterus
- Bacteria that live in the vagina can cause infection after delivery (commonly group B
strep), risk factors include anemia, bacterial vaginosis, internal monitoring of the
fetus, C-section, postpartum hemorrhage
- Symptoms include lower abdominal pain, fever and foul smelling discharge
- Uterine infection can be endometritis, myometritis or parametritis
- Can develop and cause complication of sepsis
Postpartum sepsis
I mean, this is really just sepsis after childbirth, read about sepsis and add the childbirth bit!
Endocrinology Pathology
113. Pituitary gland diseases: acromegaly, hypercortisolism (Itsenko Cushing
syndrome), hypopituitarism, diabetes insipidus. Etiology & pathogenesis.
Organ-site pathomorphology
What is the pituitary gland

- A bean-shaped structure at the base of the brain within sella turcica. Has an anterior
and a posterior part
- Anterior (adenohypophysis)
- Adrenocorticotropic hormone (triggers cortisol release from
adrenals)
- Follicular stimulating hormone (stimulates ovarian development and
spermatogenesis in females and males respectively)
- Growth hormone (growth)
- Luteinizing hormone (triggers ovulation)
- Prolactin (triggers milk production)
- Posterior (neurohypophysis)
- Oxytocin
- Vasopressin
- The anterior portion releases true hormones, while the posterior part releases
neurohypophysial hormones into the blood
- The pituitary is under the control of the hypothalamus (which sits above attached by
the stalk), which releases control hormones
Symptoms of pituitary gland diseases have three groups:

- Hyperpituitarism effects - often due to anterior pituitary adenoma
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- Hypopituitarism effects - often due to deficiency of trophic hormones (issue of

hypothalamus), possibly due to ischemia, surgery, radiation or inflammation
- Local mass effect
Acromegaly and Hypercortisolism

- Both of these are due to overproduction of pituitary hormones. Growth Hormone
in the case of acromegaly, and adrenocorticotropic hormone in the case of
hypercortisolism
- The most common cause of this is pituitary adenoma
- Increased GH is due to a Somatotroph pituitary cell tumour, the tumour can
be densely or sparsely granulated. In children increased GH causes
gigantism, in adults, increased GH causes acromegaly. Acromegaly presents
as enlarged hands and feet, possibly with joint pain, thicker skin and forehead
enlargement. Also display impaired glucose tolerance and diabetes mellitus
- Increased ACTH causes hypercortisolism, the condition is known as Cushing
syndrome. Symptoms are abdominal obesity, reddish stretched face, fat lump
between shoulders, acne, fragile skin and high BP.
- Most pituitary adenomas are sporadic (non-familial) and some do not have any
effect on the hormone production.
- Pituitary adenoma is usually well circumscribed, commonly confined by sella
turcica, although larger lesions may press on the optic chiasm. Cellular
monomorphism and no reticulin network distinguish pituitary adenoma from
non-neoplastic anterior pituitary parenchyma.
Hypopituitarism, diabetes insipidus

- Hypopituitarism occurs with loss of 75% or more of the anterior pituitary, this can be
congenital (very rare) or acquired. Most causes of anterior hypopituitarism are due to:
- Nonfunctioning pituitary adenomas
- Ischemic necrosis of the anterior pituitary
- Ablation of the pituitary (iatrogenic)
- Diabetes insipidus is illustration of posterior pituitary dysfunction, as the vasopressin
(aka Antidiuretic Hormone, ADH) secreted from the posterior pituitary and in turn acts
on the collecting ducts of the kidney tubules to promote water reabsorption. With
decreased levels of ADH secretion, less water is reabsorbed, meaning that patients
have much greater volume of urine. Diabetes insipidus can be due to a number of
causes:
- Idiopathic
- Head trauma
- Neoplasms
- Inflammatory disorders
- Iatrogenic
114. Thyroid epithelial hyperplasia. Hypothyroidism. Myxedema
The thyroid gland has two lateral lobes connected by an isthmus. During embryological
development it descends from the foramen cecum at the base of the tongue to its location on
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the anterior of the neck. We mention this as you can get ectopic thyroid tissue along this
path. The thyroid consists of lobules, which have follicles.
In response to Thyroid stimulating hormone (TSH) released from the pituitary, thyroxine
(T4) and triiodothyronine (T3) are released. While T4 is released in greater amounts, T3
has a much greater level of affinity for the thyroid hormone receptor (TR), while in the
periphery, T4 is converted to T3 as required, T3 can be thought of as the active form of
T4, this allows the body to have consistently high levels of active hormone in the periphery
as required, without the risk of toxicity. As the T4 reacts with the TR, it controls the
transcription of certain genes.
Thyroid epithelial hyperplasia

- Note - in books this is referred to as Diffuse and Multinodular goiter
- This is the enlargement of the thyroid and is the most common manifestation of
thyroid disease
- It is most often caused by iodine deficiency, causing impairment of hormone
synthesis which increases TSH levels, in turn causing hypertrophy and
hyperplasia of thyroid follicular cells and overall gross enlargement of the
thyroid
- In the vast majority of cases, the hyperplasia is sufficient compensation, and the T3
and T4 levels are steady, however where compensation fails, we have goitrous
hypothyroidism
- Goiters can be
- Endemic (where there is low natural iodine in the diet, common in himalayas
and Andes)
- Sporadic (less common, more common in females around puberty)
- Morphologically, hyperplasia can be diffuse or multinodular
Hypothyroidism
- Commonly divided into primary (an issue in the thyroid) or secondary ( an issue of
the pituitary which produces TSH)
- Most common cause is low iodine leading to thyroid epithelial hyperplasia and goiter
hypothyroidism (as above), other causes are listed below
- Developmental abnormalities, iatrogenic, AI hypothyroidism, Hashimoto
thyroiditis, Drugs, Pituitary failure (this is secondary form)
- Clinical manifestations of hypothyroidism include:
- Cretinism - hypothyroidism in pregnancy or neonatal which causes impaired
development of skeletal and CNS systems, with severe mental retardation,
short stature, coarse facial features, protruding tongue and umbilical hernia
- Myxedema is hypothyroidism in older children and adults. Manifestations
include apathy, mental sluggishness (mimicking depression), cold intolerance
and obesity. A mucopolysaccharide edematous fluid can be found across the
body under the skin and subcutaneous tissue. Bowel motility is increased,
with coarsening of facial features and pericardial effusion common.
115. Hyperthyroidism. Graves-Basedow’s disease (Toxic diffuse goiter)
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Hyperthyroidism is elevated activity of the thyroid causing increased levels of T3 and T4 in

the body, it can cause a hypermetabolic state known as Thyrotoxicosis. Technically,
Hyperthyroidism is only one cause of thyrotoxicosis but as it is by far the most common, it is
often used interchangeably. Clinical manifestations are:
- Overactivity of the sympathetic nervous system
- Warm, flushed skin with heat intolerance and weight loss (despite increased appetite)
- Stimulation of the gut causing hypermotility, malabsorption and diarrhea
- Palpitations due to tachycardia and a risk of congestive heart failure
- Nervous tremor
- Exophthalmos (only in graves)
- Can lead to thyroid storm - abrupt onset, commonl in graves, px high risk of death by
heart attack.
Causes are:
- Graves disease (below)
- Multinodular goiter
- Iodine induced hyperthyroidism
- TSH secreting pituitary adenoma
Graves
- Aka toxic diffuse goiter
- Is an autoimmune condition that affects the thyroid and is the most common cause of
hyperthyroidism and goiter.
- The body produces antibodies against TSH receptor, they bind to the TSHr and
chronically stimulate it, causing continuous production of T3 and T4, as the
antibodies are basically mimincing TSH.
- Symptoms include rapid pulse, goiter, tremor, exophthalmos, fatigue, weight loss,
heat intolerance and palpitations and pretibial myxedema (non-pitting)
- On histology we can see diffuse hypertrophy and hyperplasia of thyroid follicular
epithelial cells
116. Thyroiditis - types, pathomorphology
Thyroiditis is inflammation of the thyroid. We will address each type in turn:
Hashimoto thyroiditis (chronic lymphocytic thyroiditis)

- Most common cause of hypothyroidism in the world where there is normal iodine
- It is gradual thyroid failure due to autoimmune destruction, common in women aged
45-60
- It is a loss of self tolerance to thyroid antigens, mechanisms of damage are via CD8+
cytotoxic T cells, cytokine-mediated cell death and antithyroid antibodies. Genetics is
a significant predisposing factor.
- The thyroid is diffusely and symmetrically enlarged and microscopic examination
shows mononuclear inflammatory infiltrate with well developed germinal centers. The
thyroid follicles are atrophic and have Hurthle cells, characterised by high numbers of
mitochondria.
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- Clinical features of Hashimoto’s are those of hypothyroidism (see above)
Subacute granulomatous thyroiditis (de Quervain thyroiditis)

- Less common that Hashimoto's, found in women aged 30-50.#
- Thought to be viral in etiology (most patients have an upper respiratory tract infection
prior to onset) and can be thought of as being ‘immune related’
- Gland becomes firm, with an intact capsule, unilaterally or bilaterally enlarged.
Histology will show disruption of follicles with polymorphonuclear infiltrate and
extravasated colloid
- Clinical feature is pain in the neck, fever, malaise, enlargement of the thyroid and
possibly transient hyperthyroidism. Condition is self limiting, most patients are
euthryrotic by 8 weeks.
Subacute lymphocytic thyroiditis

- Is a painless form of thyroiditis, in a subset of patients it is postpartum. Most likely to
be autoimmune in etiology
- Presents with neck mass and features of hyperthyroidism
- Generally patients are euthyrotic within a few weeks
117. Neoplasms of the thyroid: classification, pathomorphology
The thyroid can have various benign or malignant neoplasia, as well as non-neoplastic
nodules. Here we will consider the most important neoplasia of the thyroid.
Adenomas
Benign neoplasms derived from follicular epithelium, these are generally solitary. The
vast majority are non-functioning (don’t produce hormones) but some can cause
thyrotoxicosis.
Most functioning adenomas are caused by the TSH receptor signalling pathway, which
activates a mutation and causes an overactivation of the thyroid follicles.
Typically, adenomas are solitary, spherical and compress the adjacent non-neoplastic
thyroid. They sit in a well-defined capsule, which helps differentiate it from
multinodular goiters. On microscopic examination the cells are in uniform structure.
Clinical features of adenomas are that of thyrotoxicosis (see above) and hyperthyroidism.
Carcinomas
Carcinomas are relatively uncommon. Most thyroid carcinomas are derived from thyroid
follicular epithelium, there are four major subtypes:
- Papillary carcinoma (85% of cases)
- Follicular carcinoma
- Anaplastic (undifferentiated) carcinoma
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Genetic and environmental factors are implicated in the pathogenesis of these carcinomas:
- Papillary thyroid carcinomas - activation of MAP kinase pathway is a major feature
- Follicular thyroid carcinoma - mutations in PI-3K/AKT signalling pathway
- Anaplastic carcinoma - dedifferentiation of well-differentiated papillary/follicular
carcinoma
- Medullary thyroid carcinoma - arise from parafollicular C cells, associated with
RET proto-oncogene mutation
Some brief details about each major carcinoma type:

- Papillary carcinoma
- Manifest as solitary or multifocal lesions in thyroid
- May be well circumscribed and encapsulated
- Diagnosis based on observation of nuclear features with finely dispersed
chromatin (known as ground glass or ‘Orphan Annie eye’ nuclei)
- Follicular carcinoma
- Mostly uniform cells forming small follicles, similar to normal tissue
- May be widely invasive or minimally invasive
- Anaplastic carcinoma
- Almost 100% mortality
- Fast growing bulkley masses that are highly invasive
- Contain large pleomorphic giant cells and/or spindle cells
- Derived form neuroendocrine parafollicular cells
- Multicentricity is common
- Larger lesions often with hemorrhage and or necrosis
- Amyloid deposits may also be observed
118. Hyper- and hypoparathyroidism. Etiology & pathogenesis. Organ-site

alterations. Tumors of parathyroid glands
The Parathyroid glands sit posterior and superior to the thyroid, there being four glands. The
most prevalent cell is the cheif cells which secrete p
arathyroid hormone. The parathyroid
hormone (PTH) is responsible for a number of things:
- Renal tubular reabsorption of calcium
- Urinary phosphate excretion (changing serum phosphate levels)
- Conversion of vitamin D to its active dihyroxy form in kidney which augments GI
calcium absorption
- Alters osteoclastic activity
In all cases, increased PTH increases calcium level (so it increases calcium reabsorption,
increases phosphate excretion, encourages vitamin D conversion and increases osteoclast
activity).
Hyperparathyroidism
- Primary form
- Most commonly adenoma (95%) but can be primary hyperplasia and
carcinoma - mostly genetic causes
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- Causes hypercalcemia
- Morphologically adenomas are confined to a single gland, and are
composed of chief cells. Primary hyperplasia is commonly multiglandular,
and a pattern of hyperplasia is visible
- Most common clinical picture is that of silent hypercalcemia. Other symptoms
are GI disturbances, depression, muscle weakness and polyuria.
- Note PTH will be high (this is how we identify the cause of
hypercalcemia, in case of osteoblastic diseases or vitamin D toxicity,
PTH is very low due to feedback loop.
- Secondary form
- Associated with chronic depression in serum calcium level causing
parathyroid glands to go into overdrive. Most common cause is renal
failure. Renal failure causes renal insufficiency, leading to decreased
phosphate excretion causing hyperphosphatemia, this depresses calcium
levels.
- In these cases the parathyroid glands are hyperplastic
- Clinical picture is dominated by that of renal failure. Calcium levels stay stable
as parathyroid glands are able to compensate, PTH levels are however high
Hypoparathyroidism
- Far less common than hyperparathyroidism
- Causes
- Surgically induced - due to inadvertent removal of parathyroid glands
- Congenital absence (e.g. Digeorge syndrome)
- Autoimmune hypoparathyroidism
- Clinical picture is that of hypocalcemia
- Increased neuromuscular irritability (tingling, spasms, tetany)
- Cardiac arrhythmias
- Possible seizures
119. Diabetes mellitus. Etiology & pathogenesis. Pathomorphology of organ-site

alterations. Complications.
Diabetes is a group of metabolic disorders that share the feature of hyperglycemia as a

result in defects from insulin secretion, insulin action or both. Chronic hyperglycemia can
cause secondary damage to the kidneys, eyes, nerves and blood vessels.
Diagnosis is based on one of the three:

- Random blood glucose concentration of 200 mg/dL
- Fasting glucose of 126 mg/dL
- Oral glucose teste of 200 mg/dL or more
Classification of diabetes is as follows:

- Type 1 - absolute deficiency of insulin due to pancreatic beta cell destruction due to
autoimmune attack
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- Type 2 - peripheral insulin resistance and inadequate compensatory response of

insulin secretion
Type 1 pathogenesis
- Autoimmune destruction of beta pancreatic cells
- Develops in childhood and becomes manifest at puberty, while onset is abrupt,
underlying pathogenic process has being going on for some time
- Failure of self tolerance in T cells due to mutation of HLA-D gene that encodes class
II MHC
- Additionally, environmental factors such as infections may be involved,
specifically mumps, rubella and coxsackie B
Type 2 pathogenesis
- Complex multifactorial disease with environmental factors such as diet and exercise
play a role along with genetic factors.
- There is decreased ability of peripheral tissues to respond to insulin and beta cells
become ‘exhausted’ from trying to produce the required amounts for the body,
meaning that beta cell dysfunction occurs as well.
- Insulin resistance is tightly linked to obesity
Organ site alterations and complications

General complications
- Macrovascular disease
- Diabetes rapidly increases rate of atherosclerosis
- Hyaline arteriosclerosis
- Hyaline is found deposited into the vessels
- Microangiopathy
- Diffuse thickening of basement membranes throughout the body is visible,
this is most evident in capillaries of the skin, muscles, retina and renal
glomeruli.
- It is this thickening which underlies the development of diabetic nephropathy,
retinopathy and neuropathies
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Specific organ damage

- Pancreas
- Reduction in number and size of islets
- Leukocytic infiltration of the islets
- Amyloid replacement of islets (long standing type 2)
- Eye
- Retinopathy
- Cataracts
- Glaucoma
- Brain
- Microangiopathy
- Cerebral vascular infarcts
- Hemorrhage
- Heart
- Myocardial infarction - most common cause of death in diabetics
- Kidneys (Diabetic nephropathy)
- Another common cause of death in diabetics, three lesions are encountered
- Glomerular lesions
- Renal vascular lesions
- Pyelonephritis (inc necrotizing papillitis)
- The most important pathogenic process causing these lesions is the
thickening of the capillary basement membrane
- PNS
- Peripheral neuropathy
- Limbs
- Ischemic gangrene due to peripheral vascular atherosclerosis
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120. Endocrine pancreas neoplasia. Zollinger-Ellison syndrome
Pancreatic neuroendocrine tumours (PanNETs) are rare, they ca be single or multifocal

and when malignant they are most likely to metastasize to the liver. Generally these
tumours produce insulin, but some care nonfunctional. Symptoms stem from
overproduction of insulin (causing hypoglycemia - remember, insulin triggers uptake of
glucose into the cell meaning there is less glucose in the blood). The genes responsible for
PanNETs are MEN1, PTEN, TSC2, ATRX and DAXX.
Insulinomas are the most common pancreatic neuroendocrine tumour, these are beta cell
tumours. The clinical picture is that of hypoglycemic attacks, causing confusion, stupor
and loss of consciousness. Most are cured with surgical resection. Most insulinomas are
not malignant, and look remarkably like giant islets with normal cellular preservation.
Deposition of amyloid in the extracellular tissue is a characteristic feature under microscope.
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Zollinger-Ellison Syndrome
This is a syndrome caused by a gastrinoma, a tumour in the pancreas or duodenum
causing excess secretion of gastrin which in turn leads to ulceration of the
duodenum, stomach and the rest of the small intestine. Over half of gastromas are
locally invasive or have metastasized at the time of diagnosis, and they often occur with
other endocrine tumours. Patients with persistent duodenal and gastric ulceration who do not
respond to standard therapy, should be considered possible sufferers of Zollinger-Ellison
syndrome.
121. Acute and chronic suprarenal insufficiency. Etiology, pathogenesis and

clinico-pathological correlations.
The adrenal glands are paired endocrine organs with a cortex and medulla. The cortex
synthesizes three steroids:
- Glucocorticoids (mainly cortisol - regulates metabolism, reduces inflammation)
- Mineralocorticoids (most important is aldosterone - conserves sodium and water)
- Sex steroids (estrogens and androgens)
The Medulla synthesizes catecholamines (mainly epinephrine - increase BP, muscle, HR).
Adrenal insufficiency is the decreased synthesis and secretion of the above hormones.
This can be primary or secondary (deficiency of ACTH secreted from the pituitary). There
are three general categories of insufficiency:
- Primary acute
- Primary chronic (Addison's disease)
- Secondary
Primary acute insufficiency:

- Usually as a result of Waterhouse-Friderichsen syndrome (sepsis causing adrenal
haemorrhage), withdrawal of corticosteroid therapy or stress in patients with
underlying disease
Primary chronic insufficiency
- May be autoimmune, TB related, metastatic disease, systemic amyloidosis, fungal
infection or sarcoidosis
- Autoimmune is the most common
Secondary insufficiency
- Any disorder of the hypothalamus or pituitary (e.g. metastatic cancer, infarction,
infection, radiation) can reduce ACTH output and lead to reduced adrenal hormone
secretion
Morphologically, secondary hypoadrenalism changes the adrenals to small, flattened

structures with atrophy of cells. In primary autoimmune adrenalitis we see irregularly
shrunken glands with lymphoid infiltrate into the cortex.
The clinical manifestations of all of these forms of insufficiency are:

- Progressive weakness
- Fatigability
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- GI disturbances
- Voming
- Weight loss
- Diarrhea
- In primary adrenal disease - hyperpigmentation of skin and mucosa
122. Suprarenal gland tumors - primal and secondary
This question is asking about hyperadrenalism, which is caused by tumours of the pituitary
or the suprarenals (primary or secondary).
There are three types of hyperfunction based on the layer of the cortex affected by the
tumour:
- Cushing syndrome (excess cortisol)
- Hyperaldosteronism (excess aldosterone)
- Adrenogenital syndrome (excess androgens)
Hypercortisolism and Cushing's

Hypercortisolism is typically manifested as Cushing Syndrome. Properly stated cushing
syndrome is primary hypothalamic-pituitary disease associated with hypersecretion of ACTH,
but it is by far the most common cause of hypercortisolism so the terms are often used
interchangeably
In the majority of cases the pituitary gland contains an ACTh producing microadenoma,
that does not produce a mass effect, the remaining patients have anterior pituitary
corticotroph cell hyperplasia without adenoma
Primary adrenal hyperplasias (aka ACTH-independent cushing syndrome) also causes

a percentage of cases
The morphological changes of the pituitary in cushing's are marked, we see Crooke’s
hyaline change due to accumulation of intermediate keratin filaments, we can also see
atrophy (incases where there is lack of stimulation, occurs where these is adrenal
hyperplasia or ectopic secretion), or hyperplasia (where there is ACTH dependent cushing's
syndrome). Functional adenomas or carcinomas of the adrenal cortex may also be
observed.
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Clinical features of cushing's are obesity, stretch marks, hypertension, moon faces, buffalo
hump, atrophy of fast twitch fibers, limb weakness, hyperglycemia, glucosuria and polydipsia
(mimicking diabetes).
Hyperaldosteronism
May be primary or secondary due to an extra adrenal cause. The primary form is
autonomous overproduction of aldosterone, which causes decreased renin activity.
Potential causes are bilateral idiopathic hyperaldosteronism (bilateral nodular
hyperplasia), adrenocortical neoplasms (commonly caused by solitary aldosterone
secreting adenoma known as Conn syndrome) or rarely familial hyperaldosteronism.
Aldosterone producing adenomas are almost always small, bright yellow (lipid filled)
lesion, uniform in size and shape. They have spironolactone bodies within the cytoplasm
of the cells.
Main clinical feature is hypertension.
Adrenogenital syndromes
The adrenals produce dehydroepiandrosterone and androstenedione which are
converted to testosterone in the peripheral tissues. Adrenal neoplasms can cause
increased secretion of these. Symptoms are that of reduced cortisol production (a side
effect of increased androgen production), and virilizing effects in males, and masculinization
of females.
Pathologies of the Central Nervous System

123. Inflammatory diseases of central nervous system. Meningitis, encephalitis -
types according to etiology and pathomorphology
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A word first on what injuries to the CNS look like generally. Within 12 hours of an
irreversible hypoxic ischemic insult, acute neuronal injury becomes evident on H&E
staining, there is shrinkage of nucleus, loss of Nissl substances and often the nucleus
changing shape. Many neurological disorders have specific neuronal inclusions (e.g. Lewy
bodies in parkinson's, tangles in Alzheimer's). Astrocytes are the principle cells
responsible for repair and scar formation in a process known as gliosis, astrocytes
undergo hypertrophy and hyperplasia in order to deal with insult.
Meningitis
Meningitis is an inflammatory process involving the meninges within the subarachnoid
space, where this spreads to the brain it is meningoencephalitis. Generally meningitis is
caused by bacterial or viral infection, although chemical injury can also cause it in rare
cases. Types can be as follows:
- Acute pyogenic (usually bacterial)
- Aseptic (usually viral)
- Chronic (usually TB, spirochetal or cryptococcal)
Bacterial (acute pyogenic)

- E. coli in neonates and N.meningitidis in older people
- Symptoms are that of infection with neurological impairment (headache, photophobia,
irritability, clouding of consciousness and neck stiffness)
- Bacteria on lumbar puncture
- Gross morphology shows enlargement of vessels on brain surface, with pus often
visible
- Microscopic examination shows neutrophils in entire subarachnoid space
Viral (aseptic)
- Clinical term for meningeal irritation, fever and alterations of consciousness
- Onset generally less severe than bacterial form
- CSF shows lymphocytosis with protein elevation, disease generally self limiting
- Identification of viral is neigh on impossible
TB (chronic)
- TB is by are the most common, only a moderate increase in CSF cellularity, notably
difference is inclusion of intraparenchymal mass (tuberculoma) which may be
associated with meningitis
- Subarachnoid space contains gelatinous or fibrinous exudate often at the base of the
brain
- White granules may appear over leptomeninges, arteries show obliterative
endarteritis
- Microscopic examination shows lymphocytes, plasma cells and macrophages, often
with well formed granulomas, caseous necrosis and giant cells.
Encephalitis
Encephalitis = inflammation of the brain, symptoms include headache, fever, confusion,
stiff neck and vomiting. Complications are seizures, loss of consciousness, memory loss and
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death! Types are broken down by cause (viral, bacterial, fungal, autoimmune). Most
common viral etiology is herpes simplex, most common bacterial infection is
N.meningitidis. Condition generally affects the brain parenchyma diffusely, with
perivascular and parenchymal mononuclear infiltrates, microglial nodules (note
microglial hyperplasia) and neuronophagia.
124. Cerebrovascular disease
Three major pathogenic mechanisms:

- Thrombotic occlusion
- Embolic occlusion
- Vascular rupture
The term stroke is given to all three conditions when symptoms begin acutely.
The brain is highly oxygen dependent, loss of perfusion (as all of the above cause) leads
to significant negative consequences. Deprivation of oxygen can be functional (e.g. high
altitude, anemia, CO poisoning) or ischemia.
Global cerebral ischemia

- Can be due to hypotension, possibly due to shock of all kinds
- If insult is mild, may only be transient confused state
- Most susceptible neruson are the pyramidal cells of hippocampus and neocortex
- More severe cases can cause widespread neuron death leading to brain death
- Morphologically we see brain swelling, widened gyri, decreased sulci, and
demarcation between gray and white matter
- Microscopically, there are three types neuron of changes in response to ischemia
- Early changes - neuronal cell change (red neurons) with microvascularization,
cytoplasmic eosinophilia and nuclear pyknosis and karyorrhexis
- Sub acute changes - necrosis of tissue, influx of macrophages, vascular
proliferation, and reactive gliosis
- Repair - removal of necrotic tissue, loss of organization and gliosis
- In global cerebral ischemia we also see border zone infarcts, wedge shaped areas at
distal portions of arterial territories that are damaged
Focal cerebral ischemia

- This is caused by arterial occlusion, it is what we think of when we think stroke
- Cardiac thrombi most common source of emboli
- Two categories, hemorrhagic and non hemorrhagic infarcts (red and white necrosis).
- Hemorrhagic infarcts result from reperfusion of ischemic tissue producing
multiple petechial hemorrhages
- Nonhemorrhagic result from absolute occlusion
- The morphologic changes for non hemorrhagic infarcts show a pale soft and swollen
brain early, before it becomes gelatinous and friable, followed finally by liquefaction,
leaving a fluid filled cavity. Microscopically, the pattern is as we described above for
global ischemia (early changes, sub acute changes, and repair).
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- Hemorrhagic infarcts have parallel macro and microscopic morphology but with the
addition of blood extravasation and resorption.
Intracranial hemorrhage
- Associated with hypertension, structural lesions and tumors, subarachnoid
hemorrhages are commonly due to ruptured aneurysms while subdural or epidural
hemorrhages due to trauma
- Primary brain parenchymal hemorrhage
- Mostly due to small intraparenchymal vessel rupture due to hypertension
- Can be clinically devisating or affect a small part of brain and be noticeable
- Morphologically, extra vascularised blood with compressed parenchyma.
Over time, blood becomes brown, and discoloured. Microscopic examination
shows glial changes and edema, before pigment and lipid laden macrophages
appear and astrocyte proliferation is visible in the center.
- Cerebral amyloid angiopathy
- Amyloidosis of small and medium cerebral vessels
- Greater risk of hemorrhages due to stiffer vasculature
- Associated with hypertension
- Subarachnoid hemorrhage and saccular aneurysms
- Hemorrhage into subarachnoid space due to ruptured aneurysm
- Causes massive thunder clap headache and rapid loss of consciousness
- Most occur in the anterior circulation
- Genetic element as well as environmental
- Vascular malformations
- Four types: arteriovenous, cavernous, capillary and venous malformations
- Commonly affect men, increase risk of hemorrhage
- On gross inspection look like tangled worms, microscopic examination shows
enlarged blood vessels, often with evidence of previous hemorrhage
- Cavernous malformations have loosely organised vascular channels and thin
collagenous walls
- Other vascular diseases
- Hypertensive cerebrovascular diseases - cause hyaline arteriolar sclerosis
(see above), lacunar infarcts (commonly in deep gray matter), rupture of small
penetrating vessels, and acute hypertensive encephalopathy
- Vasculitis - inflammation of cerebral blood vessels.
125. Demyelinating diseases of the central nervous system
CNS axons are ensheathed by myelin which helps to increase the speed of neural impulses,
it is most dominant in the white matter of the brain. There are two broad groups of myelin
diseases:
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- Demyelinating diseases - where normal myelin is attacked and damaged (e.g. MS)
- Dysmyelination diseases - where myelin is not properly formed to begin with
MS
- An autoimmune demyelinating disorder characterised by episodes of neurologic
defects, separated in time, with lesions separated by space
- It is defined as having two ‘sclerotic’ lesions within the CNS system
- PG/ genetic + immune. Often triggered by an infectious agent, with risk 15x greater if
a family member has, immune mediated myelin destruction has a central role.
- Predominantly a white matter disease, we see well-circumscribed, depressed,
glassy-appearing, gray lesions known as plaques .These can be active or inactive.
- Active plaques have lymphocytes and macrophages which are breaking down
myelin, they have four classes (types I-IV) based on margins and content
- Inactive plaques do not have active inflammatory cells, there is no myelin left,
and only astrocytic proliferation and gliosis
- Clinical features are that of neurologic attack, in relapse and remission pattern
Other demyelinating diseases

- Immune mediated demyelination can occur after a number of infectious illnesses, and
are thought to be due to immune cell responding to pathogen
- Two general there are two patterns
- Acute disseminated encephalomyelitis! (MY DISEASE)
- 20% fatal, others make recovery, we know the symptoms very well! :P
- Acute necrotizing hemorrhagic encephalomyelitis
- More devastating form of the above
- Neuromyelitis optica
- Inflammatory demyelinating disease of the optic nerve (previously
thought to be a form of MS)
- Central pontine myelinolysis
Leukodystrophies
- Inherited dysmyelinating diseases where there is abnormal myelin synthesis or turn
over.
- Some involve lysosomal enzymes, others peroxisomal enzymes, a few, mutations of
myelin genes
- Most are AR, some X-linked
- Morphologically, white matter is not as white, and decreased in volume, brain
becomes atrophic with infiltration of macrophages.
126. Tumors of central and peripheral nervous system

CNS tumours
- Gliomas
- Well differentiated benign tumours of brain parenchyma
- Can be astrocytomas, oligodendrogliomas and ependymomas
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- Astrocytomas can be diffuse or pilocytic. The diffuse form is the most

common, and are usually found in cerebral hemispheres. Can cause
seizures, headaches and focal neurologic defects. Morphologically,
they are fray, infiltrative tumours, some are firm, others are soft (due to
tissue necrosis)
- Oligodendrogliomas occur in middle aged patients, they have better
prognosis than astrocytoma patients, they form gelatinous, gray
masses which may have cysts, focal hemorrhage and calcification.
The tumours also contain a network of capillaries
- Ependymomas often arise next to ependymal lined ventricular system
in young people. Typically solid or papillary masses that extend from
ventricular floor, tumour cells may be elongated or perivascular
pseudorosettes.
- Neuronal tumours
- Central neurocytoma is a low grade neoplasm found adjacent to ventricular
system
- Gangliomas are tumours with a mix of glial elements (low-grade astrocytomas
+ another)
- Dysembryoplastic neuroepithelial tumour is a slow growing low grade
childhood tumour
- Embryonal neoplasms
- Medulloblastoma - located in midline of cerebellum, gray, friable and well
circumscribed. Highly cellular. Have a ‘small round cell’ appearance that is
reminiscent of progenitor cells, hence embryonal neoplasm
- Meningiomas
- Tumours that arise from arachnoid meningothelial cells, often attached to the
dura.
- Usually come to attention because of vague nonlocal symptoms or as an
incidental finding.
- May be in association with CN8 (schwannomas) or glial tumours, may be part
of neurofibromatosis type 2 disease
- There are atypical and anaplastic (malignant) meningiomas
- Familial tumour syndromes
- Tuberous sclerosis (AD)
- Von Hippel-Lindau disease (AD)
Peripheral nerve sheath tumours

- Schwannomas and neurofibromatosis type 2
- Schwannomas are benign encapsulated tumors that can occur in soft tissues,
internal organs or spinal nerve roots
- Tumors that arise at nerve root or on the vestibular nerve can be associated
with symptoms related to compression
- Most are sporadic, but 10% occur due to familial neurofibromatosis type 2,
these patients are at risk of getting multiple schwannomas
- Histologically, we see a mix of dense and loose areas (Antoni A and B),
comprised of a uniform proliferation of neoplastic Schwann cells.
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- Neurofibromas
- These are benign peripheral nerve sheath tumours, three types
- Localised cutaneous neurofibromas
- Plexiform neurofibromas
- Diffuse neurofibromas
- Unlike schwannomas these are not encapsulated, and they are mixed with
other cell types, not just schwann cells (include mast cells, fibroblast-like cells,
perineural cells), as a result the growth pattern is more haphazard. The
plexiform type affect multiple fascicles of individual nerves, the diffuse form
shows infiltrative pattern of growth within the dermis and subcutis of skin.
- Malignant peripheral nerve sheath tumours
- Mostly show evidence of schwann cell derivation
- About half are due to Neurofibromatosis type I
- AD disorder due to mutation in tumour suppressor of neurofibromin.
- Increase in malignant peripheral nerve sheath tumours, optic gliomas
and other glial tumours
- Exhibit seizures, skeletal abnormalities, vascular abnormality and
pigmented iris and skin lesions
- Traumatic neuroma is the other tumour to be aware of, this is a
non-neoplastic proliferation associated with previous injury of a peripheral
nerve
Pathologies of infectious diseases

127. Infectious diseases. Etiology & pathogenesis. Classification according to
organ site and transmission mechanism
Various categories of infectious agents:

- Prions - abnormal forms of host protein that cause transmissible spongiform
encephalopathies (including Creutzfeldt-Jakob disease)
- Viruses - obligate intracellular parasites that use host cell for replication
- Bacteria - we know about this
- Fungi - eukaryotes with thick chitin containing cell walls, generally limited to those
who are immunocompromised
- Protozoa - single celled eukaryotes that are a major cause of disease in developing
countries. They replicate intracellular (e..g plasmodium, leishmania) or extracellular
(e.g. trichomonas vaginalis)
- Helminths - parasitic worms, three groups: nematodes, cestodes and trematodes
(aka roundworms, tapeworms and flukes).
- Ectoparasite - insects (e.g. lice) or arachnids (e.g. ticks) that attach and can transmit
bacteria (e.g. Borrelia burgdorferi, agent of lyme disease from deer ticks)
Infectious agents can get into the body in a number of different ways:
- Via the skin (may be opportunistic e.g. S.aureus) often have to break through the skin
via an existing wound or vai an injection etc
- Via the GI tract - can be absorbed or release toxins that disrupt the normal GI state
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- S.aureus, V.cholerae, shigella and salmonella typhi all good examples

- Via respiratory tract - many microorganisms - e.g. influenza virus
- Via urogenital tract - bacteria ascend through the urethra
Once inside the body microorganisms can proliferate locally, at the site of infection , or
spread to distant sites by lymphatics, blood or nerves.
After transport, organisms look to be released and transmitted onwards, this may be by
shedding in the skin, release in saliva, via respiration, shedding in stool, exit via blood, urine,
STIs or vertical transmission to fetus.
The mechanism of injury is dependent on the nature of the infectious agent, below we look
at some examples:
- Mechanism of viral injury
- Replicate hat host cells expense, effectively kill the cell based on one of a
number of mechanisms: direct cytopathic effects, antiviral immune response
or transformation of infected cells.
- How the viral injury manifests depends a great deal on virulence, immune
response and viral cell tropism
- Mechanism of bacterial injury
- This may be adhesion to host cell, invasion of host cell forcing cellular lysis
(or just as transport)
- By bacterial toxins (these can be endotoxins or exotoxins - endotoxins are
elements of the bacteria themselves, exotoxins are secreted)
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Often the damage however is as a result of the bodies response to the bacteria, e.g.
granulation in the case of TB and fibrosis in the case of HBV and HCV.
The body can react in different ways to ifnectious agents:

- Suppurative (purulent) inflammation
- Reaction to acute tissue damage, with increased vascular permeability and
leukocytic infiltration of neutrophils - typical for acute infections
- Collection in localized liquefactive necrosis can form abscesses.
- Mononuclear and granulomatous inflammation
- Diffuse, mononuclear, interstitial infiltrates are a common feature of all chronic
inflammatory processes
- Which mononuclear cell predominates depends on the etiology - e.g.
lymphocytes in HBV, plasma cells in syphilis.
- Granulomatous inflammation is a distinct form of mononuclear inflammation,
evoke by infectious agents that resist eradication (e.g. m.tuberculosis)
- Cytopathic-cytoproliferative reaction
- Usually a result of viruses, due to virus inducing increased cellular
reproduction, this can cause blistering or precancerous lesions
- E.g. HPV, herpes virus
- Tissue necrosis
- C. perfringens and other organisms that secrete powerful toxins cause such
rapid necrosis the immune system barely has time to wake up
- Few inflammatory cells present,
- Chronic inflammation and scarring
- This is fibrosis as a result of injury and insult
128. Airborne transmitted infections - influenza, measles, scarlet fever, parotitis.

Organ site pathomorphology
Influenza
Influenza = single stranded RNA virus that can be type A, B or C. The type A form is a major
cause of epidemics thanks to hemagglutinin mutation, antigenic drift, that allows the virus
to morph and affect new hosts. Vaccine is available for those that are most at risk.
Some strands are particularly dangerous, H5N1 (bird flu) virus and H1N1, swine flu virus
are notable examples. Influenza virus can go on to cause influenza pneumonia. Airways
show mucosal hyperemia with lymphocyte, histocyte and plasma cell infiltrates. Various
respiratory and systemic symptoms (fever, myalgia, tiredness).
Measles
Causes an acute febrile illness with upper respiratory symptoms and maculopapular
rash, spread via air droplets, it is a highly infectious virus that can cause pneumonia,
bronchiolitis and other airway diseases.
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Microscopic observation is that of epithelial giant cells with viral inclusions, nuclei may
contain single Cowdry type A inclusion and reticuloendothelial giant cells may be found
in lymphoid tissue.
Scarlet fever
A group of diseases which can occur due to group A strep pyogenis infection. Symptoms
include swollen lymph nodes, rash (feels like sandpaper), and red and bumpy tongue.
Usually secondary to strep throat or streptococcal skin infections. The additional
symptoms (compared to simply streptococcus pharyngitis) such as rash are due to
erythrogenic toxin produced by the bacteria.
Diagnosis based on clinical findings plus throat culture or antigen detection test.
Parotitis
Inflammation of the parotid salivary gland. Most commonly due to non-infectious causes
(dehydration), can also be due to S.aureus. Bacterial causes are generally unilateral,
non-bacterial are bilateral. Associated with poor oral hygiene, symptoms include
dehydration, chills, fever, tachycardia and a risk of sepsis.
Parotitis also occurs in mumps, the most common viral cause. Paramyxovirus causes
mumps and can cause the parotid gland to swell. Can also occur in Sjogren’s
syndrome (autoimmune) and blockage (possibly due to mucus plug or tumour)
129. Insect vector transmitted infections - lyme disease, malaria, hemorrhagic

fevers. Etiology & pathogenesis. Organ site pathomorphology
Lyme disease
Lyme disease is caused by infection with spirochete Borrelia burgdorferi, transmitted by
deer ticks. It involves multiple organ failure and has three stages:
- Stage 1 - Borrelia spirochetes multiply at site of entry, causing ‘bullseye skin
lesion’ aka erythema chronicum migrans, along with a systemic fever, IgM and
IgG AB are present in skin
- Stage 2 - early disseminated stage where spirochetes spread causing
lymphadenopathy, joint and muscle pain, cardiac arrhythmias, meningitis and
sometimes CN involvement
- Stage 3 - late disseminated stage where spirochetes cause chronic arteritis and
encephalitis
- Here, histology shows chronic papillary synovitis with synoviocyte
hyperplasia, fibrin deposition and mononuclear cell infiltrates around joints
Malaria
Endemic in Asia and Africa, caused by one of four types of protozoa, Plasmodium
falciparum, which causes tertian malaria is the most important (others are P. malariae, P.
vivax and P. ovale).
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Parasites are injected via mosquitos and multiply forming schizonts in liver cells, from
here merozoites are release which affect RBCs, where asexual reproduction occurs,
and trophozoites develop.
Clinical features show:

- Fever and chills every 48-72 hours due to release of merozoites from RBCs
- Hemolytic anemia
- Release of brown hematin causes discolouration of spleen, liver, lymph nodes and
bone marrow
- Falciparum malaria often involves the brain and causes cerebral malaria
Haemorrhagic fever
Viral hemorrhagic fevers include:
- Ebola
- Marbung
- Lassa fever
- Yellow fever
All are characterised by bleeding and fever and can progress to high fever, shock and death.
Petechiae, bleeding, edema, hypotension, malaise, muscle pain, diarrhea and shock are all
common symptoms. Different pathogenesis for different fevers, but mechanisms include
liver damage, DIC and bone marrow dysfunction.
130. Infections transmitted by direct physical contact - anthrax, tetanus, rabies.

Organ site pathomorphology
Anthrax
An infection caused by Bacillus anthracis. Can occur in skin, lung, intestinal or injection
forms. Symptoms occur within a month. Anthrax is spread via bacterium’s spores which
can be breathed in, consumed or coe in through broken skin. Use of anthrax as a weapon is
the greatest risk, although it is common in Africa and central and southern asia.
The pathogenesis is thanks to the two virulence factors of poly-D-glutamic acid capsure
which prevents phagocytosis and the anthrax toxin (contains antigen, edema factor
and lethal factor).
Skin form symptoms

- Most common cause, least dangerous
- Causes a boil-like skin lesion that ulcerfies with black center (necrotic region)
- After time begins to blister, surrounding area we can see cellulitis with edema and an
almost bread like mold
Lung form symptoms

- Affects lymph nodes in lungs first, causing hemorrhagic mediastinitis with bloody fluid
accumulating in mediastinum leading to shortness of breath
- First stage of disease involves flu-like symptoms
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- Second stage (from here 90% fatal) pneumonia occurs as infection spread from
lymph to lungs
GI form symptoms
- Occasional vomiting of blood can occur, with lesions in intestines, mouth and
esophagus.
- Bacteria can spread to bloodstream and become systemic
- This is the rarest form of anthrax
Tetanus
Tetanus is a bacterial infection of Clostridium tetani characterised by muscle spasms due to
a neurotoxin. C.tetani spores are found commonly in the environment (dirt etc) and as the
bacteria are anaerobic they thrive in wounds. Tetanus affects skeletal muscle only the
tetanus toxin binds to nerve terminals in the periphery and travels to the CNS where it
fixes to gangliosides at the presynaptic inhibitory motor nerve endings, where it goes to
block the release of GABA (inhibitor) across the cleft, causing nerve impulses and muscle
spasms.
Symptoms begin with lockjaw, with chest, neck, back, abdominal muscles all to follow.
Prolonged muscular action can cause groups of muscle to spasm, known as tetany. Other
systemic symptoms of bacterial infection also occur (note tetanus has an incubation period
of usually about 10 days).
Rabies
Rabies is a disease that causes severe encephalitis, caused by lyssaviruses, exposure is
from rabid animals (usually via bite), and the virus enters the CNS ascending along the
peripheral nerves - as such the incubation time depends on the location of the bite to
the brain. After some time, the symptoms of malaise, headache and fever develop, followed
by CNS excitability (touch causes pain, violent motor responses and convulsions) and
contraction of pharyngeal musculature which can prevent swallowing. Eventually, mania and
death. There is also the slightly odd fear of water!
131. Gastrointestinal infections - salmonellosis, shigellosis
Salmonellosis
Salmonella species, members of enterobacteriaceae family (gram -ve) have two main
pathogenic species:
- Salmonella typhi (causes typhoid)
- Salmonella enteritidis ( causes salmonella food poisoning)
Very few bacteria are required to cause infection, especially in cases of patients with
decreased gastric acid (e.g. atrophic gastritis). Salmonellae have a type III secretion
system that can transfer bacterial proteins into M cells and enterocytes, that active host
cell Rho GTPases, triggering actin rearrangement and bacterial uptake into phagosomes
where the bacteria grow.
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Salmonella typhi (Typhoid fever)

- Infection most common in endemic areas
- Humans are the sole reservoir, transmission thanks to contaminated food or water
- Gall bladder colonization can cause gallstones, acute infection shows anorexia,
abdominal pain, bloating, nausea, vomiting and bloody diarrhea. Rose spots
(erythematous maculopapular lesions) are found on chest and abdomen, we may
also see complications such as encephalopathy, meningitis, seizures, endocarditis
and myocarditis.
Shigellosis
Gram -ve bacilli (fac anaerobes, nonmotile, no capsule) and the most common cause of
bloody diarrhea. Their pathogenesis is listed below:
- Highly transmissible via fecal oral route
- Shigella are resistant to the acid of the stomach, they are taken up by M cells in the
intestine where they then escape to lamina propria
- Here they infect epithelial cells via basolateral membranes and release Shiga Toxin
which inhibits eukaryotic protein synthesis and causes death
- Histology shows hemorrhagic and ulcerated mucosa (similar to Crohn's)
Clinical picture is a self limiting fever with watery, bloody stool that can last for as long as a
month. Complications are uncommon but include reactive arthritis (arthritis + urethritis +
conjunctivitis)
132. AIDS - etiology, pathogenesis, organ site damage,

pathomorphological features. Complications.
Acquired immunodeficiency syndrome (AIDS) is a retroviral

disease caused by the human immunodeficiency virus (HIV).
We see depletion of CD4+ T-lymphocytes and profound
immunosuppression. Sexual transmission is the most common
method of transmission, viruses are present in semen (cellulary
and extracellularly), and enters the body through mucosal
abrasions, HIV is also present in vaginal and cervical cells of
women so can be spread females to males (although 8x less
likely). Transmission can also be via IV drug abusers, transmission
of infected blood and mother to infant transmission.
HIV is a lentivirus and has two genetic variants (HIV 1 and HIV 2,
1 being the most common).
The main target for the virus is the immune system and CNS. Here
is the lifecycle of the virus:
- HIV binds to CD4+ or macrophages causing
conformational change allowing HIV to enter the cell
- Once internalised, the viral genome undergoes reverse
transcription, in active T-lymphocytes this becomes
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integrated into the host genome where it can remain latent for years
- Once it becomes translated, there is extensive viral replication and CD4+ cell lysis,
causing destruction of lymphoid tissue and depletion of CD4+ T-cells
Pathogenesis and progression of HIV

- Begins with acute infection, partly controlled by immune system
- Following this we have acute viremia through the body
- Advances to chronic progressive infection in peripheral lymphoid tissue with
progressive cell lysis
- HIV is highly toxic to CD4+ lymphocytes causing massive destruction (drastically
alters CD4+:CD8+ ratio)
- HIV also targets macrophages, although does not cause lysis, instead remains inside
cell for long periods
The clinical course has three stages:

- Acute primary phase (initial immune response
- Chronic phase with relative containment of the virus
- Final crisis phase with catastrophic loss of defences
Clinical presentation is wide and varied, includes increase in opportunistic infections

(those that do not usually affect people unless immunocompromised), recurrent infections,
increased risk of cancers, and a bunch of others things. There are a few things that are
worth noting:
- Kaposi sarcoma is a vascular tumour, rare in normal patients, but common in HIV
suffers (caused by herpes virus called Kaposi sarcoma herpesvirus)
- B cell non-Hodgkin lymphomas are a second common AIDS-associated tumour
- CNS involvement is common, 90% of patients at autopsy have some involvement
Morphology
- There are changes to lymphoid organs, enlarged lymph nodes in early stages have
follicular hyperplasia, with many plasma cells in medulla
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- In later stages, lymph nodes are ‘burnt out’ and atrophic, saller and with limited
inflammation due to severe immunosuppression.
133. Sepsis. Septicemia. Septicopyemia. Chroniosepsis. Organ damage

characteristics
First, Sepsis
Sepsis is an emergency, immune related disease where the body’s response to infection
causes damage to the self. Most commonly in the infection is bacterial, but can be fungal,
viral or protozoan as well, the primary infection can arise from anywhere in the body. Sepsis
is a result of both microbial and host factors, and occurs in two stages, early on we have
excessive inflammation, followed by a prolonged period of immunosuppression. Either
stage can be fatal. Sepsis occurs in those with a weakened immune system, as it relies on
the bacteria getting away from the local, and into the systemic.
In sepsis the bacterial pathogen is recognised by its pathogen associated molecular patterns
(PAMPs), by the pattern recognition receptors (PRRs) of the innate immune system. This
causes a series of signalling cascades, up regulating expression of pro inflammatory
cytokines. This triggers an uncontrolled immune response, as leukocytes are not
recruited to the specific site, but rather the entire body, effectively causing systemic
inflammation. The body detects this and tries to compensate, by shifting the
proinflammatory T helper cell 1 to TH2, known as ‘compensatory anti-inflammatory
response syndrome’. The problem with this, is that apoptosis becomes worse in the
immunosuppressive stage, and multiple organ failure ensues.
The consequences of sepsis can be:

- End organ dysfunction (aka multiple organ dysfunction
- Acute respiratory distress syndrome (fluid accumulation in the lungs)
- Encephalopathy
- Liver disruption with disruption to clotting factor synthesis
- Oliguria
- Heart failure due to cytokines that depress myocardial function
- Septic shock
Septicemia
Sepsis and Septicemia are sometimes used interchangeably, but they are separate.
While sepsis is the extreme inflammatory response to infection, septicemia is the actual
having bacteria/bacterial toxins in the bloodstream. Another way of thinking of it is that
Septicemia causes sepsis.
In relation to this part of the question, I think you just need to explain that Septicemia causes
Sepsis.
These days, septicemia has been replaced by the more useful, bacteremia.
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Septicopyemia
Septicopyemia is Septicemia + Pyaemia. As we’ve covered septicemia above, here we’ll
consider pyemia.
Pyemia is septicemia caused by a pus forming bacteria, what is a pus forming

bacteria I hear you ask, mostly staphylococcus aureus. S.aureus can cause the
formation of pus (remember, dead neutrophils + protein-rich liquor puris) which then emboli
and become septic thrombi. These septic thrombi travel around the body before settling in
organs and developing multiple small abscesses inside one or more organs.
Common locations include lungs, liver, brain, kidney and spleen.
Chroniosepsis
It’s never a good sign when the first hits on google are a Russian and Polish article from 59
and 69 respectively!
All I can find is something saying that chroniosepsis is a form of sepsis that is long in
development with decreasing reactivity of organism, it is caused by a septic wound
that does not heal (eg chronic tonsillitis). Symptoms include chronic exhaustion and
intoxication, and lead to brown atrophy of heart and liver with atrophy and hemosiderosis of
spleen …. That’s it.
134. Primary pulmonary tuberculosis. Primary TB complex morphology.

Complications. Progressive hematogenous tuberculosis - generalised or
pulmonary
Tuberculosis is a communicable chronic granulomatous disease caused by

mycobacterium tuberculosis, it commonly involves lungs but can affect any part of the body,
causing tuberculous granulomas which undergo caseous necrosis.
Primary TB is the form of the disease that develops in previous unexposed (and therefore
unsensitized) patients, it usually affects the immunocompromised. TB causes a
hypersensitivity reaction which is the cause of the tissue destruction. Macrophages are
activated after the consumption of the bacteria, here they survive and proliferate. This
macrophage goes on to trigger T-cells which in turn a ctivate more macrophages and
cause the formation of the hypersensitivity granuloma.
Primary TB almost always beings in the lungs, as sensitization develops, a gray-white

inflammatory region knowns as Ghon focus develops, this focus then undergoes caseous
necrosis, in combination with the parenchymal lesion and nodal involvement we know this
as Ghon complex. During the first few weeks there is then dissemination to other parts of
the body. After this, the Ghon complex undergoes fibrosis and calcification (known as Ranke
complexes), generally no secondary lesions occur outside of the lungs in primary TB.
Histology of the active sites show granulomatous inflammation with caseating and
noncaseating granulomas with giant cells. In rare cases, primary TB can develop to
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progressive primary TB, where there is massive hematogenous dissemination to

organs such as the spleen and liver in what is known as miliary TB, but this is rare in the
primary form, and generally reserved for secondary TB, however its in this question, so
apparently we’re going to talk about it, see below, also look at the typical image of a
tuberculoma.
In less than 5% of cases we get progressive primary TB, this includes the following:
- Primary caseous pneumonia - local extension of Ghon focus to entire lobe/
segment, it appears yellow-gray with caseous necrosis and can turn to liquefaction
- Tuberculosis bronchopneumonia - secondary extension of Ghon focus, involves
the entire lung parenchyma, especially at base of the lung
- Miliary TB - due to hematogenous dissemination of Koch bacilli to lung or distant
sites such as the kidneys, liver, spleen and meninges. These present as many small
nodular lesions, well defined, and yellow in colour across the whole surface of the
organ.
135. Secondary pulmonary tuberculosis - classification, organ site damage.

Microscopic & gross pathomorphology
Right, secondary TB, also known as reactivation TB, it is the pattern of disease that occurs
in a previously sensitized host. It may be a new infection to someone who has already
been affected, but more commonly it is reactivation of the dormant primary lesion
decades after initial infection. Only 5% of primary TB suffers get affected by secondary TB.
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Secondary TB is initially confined to the upper lobes of the lung, with the lesion in the
apical pleura, with central caseation and p
eripheral fibrosis. Localised apical secondary
TB may heal with fibrosis or progress to progressive pulmonary TB (as mentioned above).
In progressive TB we see apical lesion enlarge, become caviated,with the cavity lined by
caseous material, with blood vessel erosion and hemoptysis. These cavities often
remain many years after the event. Pulmonary Miliary TB then occurs when organisms
drain through lymphatics into venous return and then into right sided pulmonary
circulation, causing ‘millions’ of scattered lesions. We can also have systemic miliary TB,
when we get scattering throughout the body (see above). Remember these milliary lesions
contain lymphocytes, plasma cells and macrophages.
Lymphadenitis is the most frequent form of extrapulmonary TB, occuring in the cervical
region. It tends to be unifocal, with no extranodal diseases associated.
Tuberculosis meningitis
A type of meningitis that manifests with general CNS signs and symptoms. Moderate
increase in CSF cellularity, with mononuclear cells, protein level is elevated. Can also cause
tuberculoma in the brain which may trigger meningitis.
Tuberculosis osteomyelitis
Mycobacterial infection of the bone is a significant problem in developing countries. Bone
infections complicate 1-3% of all pulmonary TB cases, arriving from the bloodstream,
organisms target long bones and vertebrae. Lesions can be focal or multifocal. TB of the
vertebral bodies is clinically the most severe, causing vertebral deformity, collapse and can
cause neurological disorders.
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136. Acquired and congenital syphilis. Etiology & pathogenesis. Stages of

development. Primary syphilitic lesion. Organ site damage.
Syphilis is a chronic infection caused by Treponema pallidum (a spirochete), african

americans are 30x more likely to be affected. Organism is transmitted via contact of
mucosal lesion in sexual partner in primary or secondary stages, or across the
placenta from mother to fetus. Widespread dissemination occurs within days, even before
the appearance of the primary lesion. Below we will look at the stages and symptoms of
syphilis.
The first stage is the primary stage (average of 21 days after infection). Here a primary
lesion known as chancre appears at the point of spirochete entry. This resolves
spontaneously after 4-6 weeks. It is a ‘hard chancre’ in contrast to some differential
diagnosis and in males is generally on the penis, in females, the vagina or uterine cervix.
It begins as a firm papule, which becomes a painless ulcer. It is accompanied by
inflammatory infiltrate rich in plasma cells.
The secondary stage occurs about two weeks after the chancre has resolved. It manifests as
generalised lymph node enlargement and mucocutaneous skin lesions (usually
symmetrical and maculopapular), often involves palms and soles of feet. Condylomata
lata, a rash on moist skin areas, may also occur. The mucocutaneous lesions show
proliferative endarteritis with lymphoplasmacytic infiltrate, with spirochetes abundant,
these lesions are highly infectious.
The chancre and the mucocutaneous lesions are a result of proliferative endarteritis, that
is the inflammation of the intima of the artery as a result (it is thought) of the host
immune response that activates endothelial cell activation and proliferation, leading to
perivascular fibrosis and luminal narrowing.
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137. Tertiary syphilis. Pathomorphology of syphilitic specific inflammation

(gumma). Visceral changes. Neurosyphilis.
Tertiary syphilis is the third stage of the above process, occurring over a year after an
untreated infection in about ⅓ of patients. Complications related to this phase include three
forms: Cardiovascular syphilis, Neurosyphilis and benign tertiary syphilis. These can
occur together or separately.
Cardiovascular syphilis is specifically syphilitic aortitis, the most common of all

complications. Syphilitic aortitis is inflammation of the aorta, beginning with the
outermost layer (adventitia), SA worsens and affects the blood vessels that supply the
aorta itself (vasa vasorum). Vasa vasorum undergoes hyperplastic thickening of wall and
causes ischemia to other ⅔ of aorta, this causes smooth muscle cells to die and leads to
aortic aneurysms.
Neurosyphilis accounts for 10% of tertiary cases of syphilis, it is more common in those
who are immunocompromised (e.g. HIV). The infection can produce chronic meningitis
(meningovascular neurosyphilis), involving the base of the brain with an obliterative
endarteritis rich in plasma cells and lymphocytes. We can also see parenchymal
involvement, with loss of microglia. Clinical manifestations are loss of mental and
physical function with severe dementia. Tabes dorsalis is another form of the disease,
resulting from damage to sensory nerves in dorsal roots that produce impaired
proprioception and ataxia, with loss of pain sensation.
Benign tertiary syphilis is marked by the formation of gumma

at various sites, these are generally lesions on liver, bone,
skin and mucous membrane of the upper airway, but can
appear anywhere. There are rarely any spirochetes in these
gummas, they are a form of granuloma, with a firm, necrotic
center surrounded by inflamed tissue, with the center often
become hyalinized prior to coagulative necrosis. Histologically,
we see giant multinuclear cells, a peripheral zone with
fibroblasts and capillaries, as well as our lymphoid and
plasma cell invasion.
166/166

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Pathology Syllabus Notes

Pathology Syllabus Notes 1

Pathology can be seen as having two main objectives:

Basic terminology, purpose, tasks, methods

The primary methods of Pathology are:

2. Cellular injury; common causes and mechanisms

Cells exist in ​homeostasis​. Where they are subject to ​stress

Other important causes include:

These problems cause the cell to become nonfunctional, this

3. Reversible cell injury due to compromised ionic transfer (cellular swelling):

- Fatty change (increase in number of large lipid vacuoles in cytoplasm due to

Reduction in ATP results, in fact, in four significant cellular changes:

Macroscopically we see a change in ​colour to pallor​, increased ​turgor ​(hydrostatic

4. Lipid accumulation in parenchymal and stromal cells. Lipid phagocytosis.

There are four pathways for abnormal intracellular accumulations:

Lipid accumulation is most common in

Other lipid accumulations include:

5. Complex lipid accumulations: lipidosis

Lipidosis is a group of ​inherited metabolic disorders​ where harmful amounts of fats or

There are two main classifications of lipidosis:

- Non-sphingolipid related disorders

Diagnosis of lipidosis is done through ​clinical examination, biopsy, genetic testing,

6. Abnormal intracellular glycogen accumulations. Glycogenoses

Excessive intracellular deposits of glycogen are associated with ​metabolism abnormalities

a. Any other enzymopathy related to glucose metabolism

7. Hemoglobin-derived pigment accumulations. Hemosiderosis. Types of

Systemic build up can be a product of:

Meanwhile, ​excess local iron can be as a result of a hemorrhage​, such as a bruise,

There are three main types of Jaundice:

8. Non-hemoglobin derived pigment accumulations: melanin, lipofuscin

Melanin ​is an endogenous ​brown-black pigment​ produced by ​melanocytes ​located in the

On the reverse, some conditions are the product of ​decreased melanin​:

- No tirosinase enzyme therefore no production of melanin in melanocytes

Meanwhile ​Lipofuscin ​is an ​insoluble brownish-yellow granular material​ that

9. Exogenous pigments - types, organ sites

10. Extracellular accumulations: hyalinosis, fibrinoid swelling

We classify accumulations in the ECM as follows:

There are three main forms of Fibrinoid swelling

Secondly, ​fibroids forming as a product of plasma protein accumulation​, in ​malignant

11. Extracellular accumulations: amyloidosis. Types of amyloidosis, pathogenesis,

Amyloidosis is a ​product of protein misfolding​, leading to ​mutant proteins​ (like in X-men,

Pathogenesis​: Amyloidosis is the product of the following chain

Spleen (​NOTE SLIDE​):

12. Extracellular accumulations of calcium and uric acid salts

Macroscopically calcium deposits are visible as fine white granules​ while

Deposition of urates in ECM

13. Metabolic and structural abnormalities of collagen, elastin and proteoglycans.

Collagen disorders are generally the ​product of genetic defects or nutritional

Increased collagen synthesis

- Product of FBN1 gene mutation

There are two main types of disorders associated with elastins:

- This reduces activity of ATP dependent Na​+​/K​+​ pumps

Necrosis - Types of Necrosis

There are five types of Necrosis, these are:

Histologically Fibrinoid necrosis is seen as a ​bright pink amorphous structure when

Apoptosis is an integral part of a healthy organism. In neonates, during development, ​tissue

15. Ischemic necrosis - infarction. Morphogenesis. Types of infarctions - anemic,

An ​infarction is obstruction of the blood supply to an organ or tissue​ (generally by

We can also divide infarcts based on organ site:

16. Clinico-anatomical types of necrosis: gangrene, decubitus, sequestration

Clinical forms of necrosis

Decubitus ulcer (pressure sore)

Such ulcers are more common in the ​elderly and bedridden​.

Cells exist in homeostasis. Where they are subject to stress

Macroscopically we see a change in colour to pallor, increased turgor (hydrostatic

Lipidosis is a group of inherited metabolic disorders where harmful amounts of fats or

Diagnosis of lipidosis is done through clinical examination, biopsy, genetic testing,

Excessive intracellular deposits of glycogen are associated with metabolism abnormalities

Meanwhile, excess local iron can be as a result of a hemorrhage, such as a bruise,

Melanin is an endogenous brown-black pigment produced by melanocytes located in the

On the reverse, some conditions are the product of decreased melanin:

Meanwhile Lipofuscin is an insoluble brownish-yellow granular material that

Secondly, fibroids forming as a product of plasma protein accumulation, in malignant

Amyloidosis is a product of protein misfolding, leading to mutant proteins (like in X-men,

Pathogenesis: Amyloidosis is the product of the following chain

Spleen (NOTE SLIDE):

Macroscopically calcium deposits are visible as fine white granules while

Collagen disorders are generally the product of genetic defects or nutritional

- This reduces activity of ATP dependent Na+/K+ pumps

Histologically Fibrinoid necrosis is seen as a bright pink amorphous structure when

Apoptosis is an integral part of a healthy organism. In neonates, during development, tissue

An infarction is obstruction of the blood supply to an organ or tissue (generally by

Such ulcers are more common in the elderly and bedridden.

Firstly, what is a hemorrhage, simply put, hemorrhage is an escape of blood from a

Endoluminal injury can be the result of hypercholesterolemia, hypertension, smoking,

Plasminogen is first formed in the liver, and

Chronic inflammation is inflammation over a period of weeks, months or years. Typically

Pathological forms of immune reactions.

Direct rejection (cells) pathway:

There are three types of Transplant rejection:

Fibrosis (and remodelling) - replaces tissue with connective fibrous tissue.