Inflamasi

Inflammation classically describes four key signs - each of which have

a latin derivation. 
Calor or heat, dolor or pain, rubor or redness, and tumor or swelling. 
Sometimes these four signs combine to cause a fifth sign, which is functio laesa or
temporary loss of function due to pain or swelling. 
Okay - so inflammation usually starts with some stimuli, like a pathogen. 
Now, even though pathogens are a common cause of infection which can lead to
inflammation, inflammation can be caused by other things as well like toxins and
trauma. 
For example, after an intense workout, your muscles may feel sore - that's due to
inflammation trying to repair your overused muscle fibers. 
Ultimately, the goal of inflammation is to respond to the stimuli and restore balance. 
Oftentimes that includes eliminating the cause of tissue injury, clearing out necrotic
or dead cells, and starting tissue repair.
Broadly speaking, inflammation can be triggered by external and internal factors. 
External factors can be non-microbial or microbial. Non-microbial factors include
allergens, irritants, and toxic compounds.
Now, the two main microbial factors that trigger inflammation are virulence
factors and pathogen associated molecular patterns or PAMPs. 
Virulence factors are molecules that help pathogens colonize tissues and cause
infection. 
PAMPs are small molecules with conserved patterns that are shared across many
different pathogens, including bacterial wall components
like peptidoglycan, lipopolysaccharide or LPS, and lipoteichoic acid, and fungal wall
components like mannan.
For intracellular pathogens, like viruses, PAMPs might include the
viral RNA or DNA. 
Our immune system recognizes virulence factors and PAMPs as foreign substances,
and can trigger an inflammatory response against them. 
Now, in terms of internal factors, it turns out that there’s an endogenous equivalent
to PAMPs, called damage associated molecular patterns or DAMPs. 
DAMPs are intracellular proteins that get released when a cell’s plasma
membrane is injured or when a cell dies. 
So DAMPs are a signal that there’s serious cell damage and they trigger
inflammation. 
Now, PAMPs and DAMPs are recognized by Pattern Recognition
Receptors or PRRs, which are cell surface receptors on various leukocytes that help
to activate those cells and spark the inflammatory response, which can be thought of
as the innate immune system. 
Key features are that this response is non-specific - meaning that PRRs don’t
distinguish one specific pathogen from another, although they can distinguish
between broad categories like viruses from bacteria. 
Also, the response is really fast - occurring within minutes to hours, and there’s no
memory associated with innate responses.
Generally speaking, there are two main types of leukocytes: granulocytes which
include neutrophils, eosinophils, basophils, and mast cells and agranulocytes which
include lymphocytes and monocytes, which can differentiate
into macrophages or dendritic cells. 
The inflammatory process usually begins with either macrophages or mast cells,
both of which are found in the tissues. 
When there’s tissue damage, these cells respond to the PAMPs or DAMPs. 
Mast cells have granules containing different inflammatory mediators
like histamine, serotonin, cytokines, and eicosanoids, such
as prostaglandins and leukotrienes. 
These inflammatory mediators act on the endothelial cells surrounding
the capillaries nearby, causing them to separate from each other. 
In addition, macrophages - which are the garbage truck of the body - begin to eat up
invading pathogens. 
The release of cytokines causes capillaries to get larger, and increase vascular
permeability, allowing plasma proteins and fluids to leave the circulation. 
Endothelial cells also help spur on this process by releasing nitric oxide, which helps
vasodilate the capillaries and make them more permeable. 
In addition, endothelial cells express more adhesion proteins to help leukocytes that
are floating by in the blood to attach and roll along the vessel wall until they reach
the injured site. 
In particular, neutrophils get attracted to the site of infection by
the chemokines and microbial products. 
The neutrophil then begins to squeeze through the gaps between two endothelial
cells, until it reaches the other side - this is called extravasation. 
It’s a bit like squeezing between two fence poles to sneak into an amusement park,
rather than paying admission. Not saying that you should do that. 
Now next, the leukocyte follows a gradient of inflammatory mediators, to get to the
site of inflammation. 
Neutrophils are the first leukocytes recruited during the acute inflammatory process,
and they’re like hungry athletes - they immediately start phagocytosing or
eating pathogens and damaged cells.
Neutrophils take in a lot of pathogens quickly - like a vacuum - and then
commit suicide - destroying themselves and all of the pathogens they’ve taken in. 
Now while this is all happening, there’s also a family of soluble proteins called
the complement system.
The complement proteins most often get activated in the presence of antibodies
bound to pathogens, or by molecules on the pathogens. 
Once these complement proteins are active they help attract leukocytes, and help
with opsonization, meaning that they can bind to microbes so that leukocytescan
more easily phagocytose them - a bit like sticking a fork in a meatball so that it
doesn’t slip away! 
Some of the complement proteins also kill pathogens by directly forming a channel in
their membrane - literally punching a hole in it. 
All the while, dendritic cells continue to phagocytose pathogens and present bits of
them to T lymphocytes. 
This activates the adaptive immune system, which kicks in after a few days. 
If the stimulus for all of this inflammation was a cut or scrape,
then platelets and clotting factors from plasma reach the area and clot the wound. 
This helps stop the bleeding, prevents pathogens from entering the bloodstream,
and provides a framework for tissue repair. 
In sum, all of these factors contribute to the heat, pain, redness, and swelling that’s
classic for inflammation.
Now, the inflammatory response ends with tissue repair. 
Macrophages are recruited to eat up dead and dying cells, so that the tissue can
make room for new cells. 
This is followed by angiogenesis, which is the formation of new blood vessels, and
that’s triggered by growth factors released by macrophages. 
These newly formed blood vessels are temporary, meaning that once the wound has
healed, these new vessels regress.
Finally, there are fibroblasts, which come into the area of inflammation and
synthesize collagen to help with wound healing. 
Overall, if there’s only mild damage, then the tissue regenerates back to its normal
healthy state, but if there’s severe damage, then the damaged cells get replaced by
a non-functional fibrous scar.

Summary
Alright, as a quick recap, inflammation is a complex response to harmful stimuli
which could be from a pathogen, but also could be from trauma or toxins. 
The response involves blood vessels dilating and becoming more permeable, and
attracting more immune cells and fluid into local tissue. 
The classical signs of inflammation are heat, pain, redness, swelling and they can
lead to a loss of function. 
The inflammatory response ends with wound repair and resolution, either restoring
the initial tissue integrity, or leaving a fibrous scar.
Ischemia
Hypoxia, or lack of oxygen in cells and tissue, can happen in a number of ways,
and ischemia's one of them. 
Ischo- means “restraint” or “suppression”, and -emia refers to the blood,
so ischemia must mean some kind of suppression or reduction of blood flow to an
organ or tissue. 
And blood carries oxygen right? So when there’s a reduction in blood flow to cells,
that also means there’s a reduction of oxygen to those cells, and this is due to
lowered blood flow in the blood vessels.
This lowered flow could be from something blocking the blood from the inside, or it
could be something compressing the blood vessel from the outside. 
An example of something blocking the blood vessel from the inside is a thrombus,
also known as a blood clot, these are solid clumps of platelets and fibrin that
obstruct blood flow. 
Ischemia resulting from something outside the blood vessel is traumatic injury, which
can cause inflammation and swelling that physically applies external pressure to the
blood vessel, compresses it, and restricts blood flow. 
Alright, so let’s say this is your artery, and it’s like the one-way highway leading all
these red-blood-cells into the city, which is like a major organ in the middle here, so
maybe this is organ-apolis. 
These red blood cells are super pumped for their day where they can drive around
the capillaries, like the smaller city streets, and supply the city with fresh oxygen and
pick up waste. 
And this organ-apolis is made up of thousands of cells, like homes, that use up the
oxygen and create waste that needs to be picked up, the deoxygenated blood cells
drain out through different small streets which are the veins and go back towards the
heart. 
So one way this organ-city could become ischemic, is if there’s some obstruction to
arterial flow into the tissue. Now only a few red-blood-cells can get in at a time. 
You might imagine that organ-apolis sees a lot less blood and a lot less oxygen, and
becomes ischemic!
A super important and well-known example of this
arterial ischemia is atherosclerosis, where plaque builds up in the arteries going to
your heart tissue, which blocks arterial flow, reduces the amount of blood and
oxygen that make it to your heart tissue, and causes ischemic heart disease. 
Since you can have a blockage of the red blood cells coming in, you can also have a
blockage of red blood cells going out, leading to a decrease in blood drainage on the
venous side. 
So in this case, you’ve got a major obstruction in the venous highway leaving the
city, so say these are like the veins draining blood out of organ-apolis.
All these workers are getting into organ-apolis, but they can’t leave because there’s
a blockage heading out, and traffic gets majorly backed up, causing flow to slow
down throughout the whole city! 
This again leads to less oxygen to the tissues and ischemia. 
Thinking about an organ, it might get so congested that pressure can rise causing
fluid to get forced out of the blood vessels and into the tissues generating edema.
This whole example is very similar to Budd-chiari syndrome, where the hepatic
veins that drain blood out of the liver are blocked by a thrombosis, or a clot, and now
blood can’t flow through the liver and the liver tissue becomes ischemic and can lead
to liver edema and hepatomegaly, or enlargement of the liver.
If the oxygen supply is low enough for long enough, it can cause cell death, and if
enough cells die in a region of tissue we would call that tissue necrosis
and infarction. 
In some cases, there are areas of tissue that are getting close to infarction, as cells
begin to die off, but they are still able to get saved if they receive blood. 
This high-risk area that’s teetering on the brink of death is called
the ischemic penumbra. 
In some cases, there are two arteries serving a single area of tissue. 
And, this goes against how we often think about tissue as being served by a
single capillary bed from a single artery, but when you think about it in three-
dimensions, there can be a lot of overlap. 
If there are these secondary or collateral arteries going to the area then there might
be enough blood flow to keep the penumbra alive for a while. 
Over the course of weeks to months, these secondary arteries can even grow in size
to bring through more blood to that area, a bit like disaster relief; this process is
called collateralization. 
So if blood flow to an organ is blocked all of a sudden, a super important concept to
keep in mind is called time to reperfusion.
This refers to the importance of re-establishing perfusion to the affected organ before
the cells die and the ischemia becomes irreversible. 
Remember that perfusion and blood flow are slightly different; blood flow is
the volume of blood flowing per unit time, like L / min. 
Perfusion is like a measurement of how much blood is flowing to a chunk of tissue
per time, so it might be given in L per min per gram of tissue. 
So as an example, if you compared the total blood flow to the kidneys with the
total blood flow to the liver, it’d be higher to the liver because the liver’s a lot larger. 
But if you took a 10 g cube of liver tissue and compared it to a 10 g cube of kidney
tissue, the kidney actually has higher perfusion, since it has more blood vessels
packed into its cube. 
Now, back to reperfusion, if perfusion to the area is re-established quickly enough,
then it’s possible that the ischemia is reversible because the cells were dying but
they’re not dead. 
If too much time has passed and the cells have actually died, then the ischemia is
irreversible since you can’t bring back dead cells. 
One example of irreversible ischemic damage is something like a heart attack,
or myocardial infarction, where an artery supplying a specific part of the heart with
blood becomes blocked, causing death of that part. 
Depending on the area that’s affected, this could cause serious heart dysfunction,
like if enough of the heart’s ventricle was damaged, it might not be able
to pump blood as well anymore.
free radical and cellular injury
Electrons in an atom are present in spaces called orbitals, and each orbital can fit
different pairs of electrons. 
Free radicals are molecules with an unpaired electron in their outer orbital. 
Now, electrons don't like to be lonely so free radicals have a habit of
stealing electronsfrom any molecule they come across to make themselves stable. 
This causes the victim molecules to be less stable which is why free radicals are a
problem. 
Now, a free radical is formed when any molecule gains or loses an electron. 
In the body, free radicals can be generated physiologically, which means as a part of
the normal metabolic processes; or pathologically, which is due to some disease. 
A major physiological source of free radicals is cellular respiration, which is also
called oxidative phosphorylation. 
Oxidative phosphorylation is the body’s process of making ATP through the electron
transport chain. 
This chain is made up of electron carriers, called complexes, embedded within
the inner mitochondrial membrane which pass electrons along like the baton in a
relay race. 
Together, they form the electron transport chain, which pass electrons from complex
to complex. 
The final step of this process involves a molecule called cytochrome c oxidase,
sometimes known as complex IV, which transfers electrons to molecular oxygen, or
simply O2, which then splits into two oxygen atoms. 
The transferred electrons make the oxygen atoms electronegative enough to grab
two protons, or H+ ions, each from the mitochondrial matrix - making two molecules
of H20. 
Normally, four electrons are required to convert O2 into two molecules of water. 
But when less than four electrons are transferred to oxygen, then it will have
unpaired electrons in its orbitals, giving rise to free radicals. 
Since these are formed from oxygen, they’re collectively called reactive oxygen
species, or simply ROS. 
Okay so if oxygen is given one electron, it becomes superoxide (so O2 with a little
dot for its extra electron).
If it gets two electrons, it becomes hydrogen peroxide, or H2O2, and then
3 electrons, it’s hydroxyl radical.
There are also pathological conditions where free radicals can be generated. 
First, they can be produced during an inflammation
by phagocytes like macrophages and neutrophils. 
When a pathogen invades the body, the phagocyte gobbles up the pathogen forming
a phagolysosome. 
These phagocytes also have an enzyme called NADPH oxidase, which gets
activated by the lysosomal enzymes, causing NADPH to undergo oxidation, and lose
two of its electrons. 
Nearby oxygen molecules can grab these electrons to form superoxide ions, or
O2- ions. 
Another enzyme, superoxide dismutase, can take these ions and combine them
with hydrogen ions to form hydrogen peroxide, or H2O2.
This process of producing superoxide ions and hydrogen peroxide is called
the respiratory burst. 
These ions and molecules destroy pathogens by breaking down their cell
membranes and damaging their proteins.
Another way free radicals can be generated is through exposure to ionising
radiations like ultraviolet light or X-rays. 
When the radiation hits the water in the tissues, it knocks off an electron. 
So, if we go back to the previous sequence, and go backwards here from water,
you’ll end up at the hydroxyl radical.
Free radicals can also be generated when there’s a build up of metals like copper or
iron in the body.
For example, hemochromatosis is a condition where unusually high amounts of iron
is absorbed. 
All this extra iron, undergoes the Fenton reaction, where molecules of iron 2+
are oxidizedby hydrogen peroxide, producing iron 3+ and the hydroxyl radical and
hydroxide ion as byproducts; now, iron 3+ can than be reduced back to iron 2+
via hydrogen peroxide again, creating a peroxide radical and a proton, and then the
cycle repeats, creating this like endless loop of free radical generation.
So, over time, all these deposits of iron slowly damage the cells in the various
organs by free radical generation, that case cell death and then lead to
tissue fibrosis. 
Free radicals are also produced following ischemia, or reduced of blood flow to an
organ or tissue. 
At the cellular level, ischemic injury can lead to the production of ROS by
the mitochondria. 
If blood flow returns to the ischemic tissue, it's called reperfusion, which brings along
with it more oxygen. 
Unfortunately, though, all this oxygen reacts with the ROS formed during ischemia to
form more, which worsens the cell damage, called reperfusion injury.
Finally, free radicals can also be generated when chemicals or medication that enter
the body are being metabolised by the liver. 
For example, acetaminophen is an analgesic medication metabolised by the liver
enzymecytochrome P450. 
During this process though, free radicals like phenoxyl free radical and N-acetyl-p-
benzoquinone imine can be generated, and so when high doses
of acetaminophen are taken, it can cause massive death of tissue in the liver, and
this is mainly from free radical damage. 
Another example is the chemical carbon tetrachloride, or CCl4 which was used in
the cleaning industry. 
When this guy enters the body, P450 enzyme converts it into trichloromethyl radical,
or CCl3, which can again cause damage to the liver.
Since the body generates free radicals even under normal conditions, there are
certain defence mechanisms in place to keep them in check. 
One of them is antioxidants like vitamin A, vitamin C, and vitamin E, which do the
opposite of free radicals by donate electrons, and protect the cells. 
There’s also another molecule in our body called glutathione which acts as
an antioxidantand goes around and neutralizes H2O2. 
In order to function, glutathione needs to be in the reduced state where it
can donate an electron to the H2O2 and convert them into harmless water and
oxygen.
However this causes the glutathione to become oxidized, so before it can get back to
work, an enzyme called glutathione reductase will use an NADPH as
an electron donor and and reduce the oxidized glutathione back into its working
state. 
After giving up its electron, the NADPH will become NADP+. 
So to replenish the supply of NADPH, we have the glucose-6-phosphate
dehydrogenaseenzyme, or G6PD, which reduces NADP+ back to NADPH
by oxidizing a glucose-6-phosphate. 
Glucose-6-phosphate is a metabolite of glucose so we usually have a ready supply
of this molecule as long as we are not starving. 
Another defence mechanism is metal carrier proteins which bind to the metal
ions and help in transporting or storing them.
This way the ions are sort of like hidden away and so, are not able to generate free
radicals. 
For example, transferrin which binds to iron, and ceruloplasmin which binds
to copper. 
And finally, there are also free radical scavenging enzymes which convert the free
radicals into harmless substances like water. 
Superoxide dismutase, takes superoxide and converts it into hydrogen peroxide.
Catalase converts hydrogen peroxide into water in peroxisomes, and glutathione
peroxidase does the same in the cytoplasm.
When the amount of free radicals produced overwhelms the defence mechanisms,
cell damage starts to occur. 
Free radicals can react with the lipids in the cell membrane, causing lipid
peroxidation. 
For example, let’s say a hydroxyl radical has attacked this particular lipid molecule. 
This molecule is now left with an unpaired electron, so it in turn grabs
an electron from the next lipid molecule, setting up a sort of chain reaction which
ends up damaging the cell membrane. 
Free radicals can also cause oxidative modification of proteins, which affects the
function of enzymes and other structural proteins. 
Oxidation of DNA can cause breaks in the DNA strands, and can also introduce
mutations which increase the risk of cancer.
Summary All right, as a quick recap… Free radicals are chemical species with an
unpaired electron, which can damage the cells by oxidizing the lipids, proteins, and
even the DNA. 
They are produced in the body physiologically by the electron transport chain,
and pathologically during inflammation, exposure to ionizing radiation, metabolism of
chemicals or medication like acetaminophen, build up of metals like iron or copper,
and reperfusion of ischemic tissue. 
Free radicals are normally kept in check by antioxidants, metal carrier proteins and
free radical scavenging enzymes.
Necrosis and apoptosis
Generally speaking, cells have two ways to die. One way is by apoptosis, which is a
form of programmed cell death - a bit like cellular suicide. 
The second way is by necrosis, which is when cells die due to injury or disease. 
Overall, apoptosis occurs much more often than necrosis. 
One example is when old skin cells undergo apoptosis, and get replaced by new skin
cells. 
Another example is in our hands and feet during fetal development. 
Initially, human hands and feet look like duck's feet, with webs of skin connecting the
fingers. 
But the cells in the webbing undergo apoptosis and that allows us to form individual
digits that allow us to pick our nose and play the piano. 
In contrast, necrosis occurs less frequently, and an example of that is when a blood
vessel that goes to your big toe gets clogged causing ischemia, which is where
oxygen and nutrients can’t reach the cells. 
As a result, those cells begin to die, turning your big toe a nasty shade of black. 
In apoptosis, there are two activating mechanisms - the intrinsic pathway, also called
the mitochondrial pathway, and the extrinsic pathway, also called the death receptor
pathway.
The intrinsic pathway occurs when a cell is exposed to stress like radiation, hypoxia,
or low oxygen, a high intracellular concentration of calcium ions, or oxidative stress,
which is where reactive molecules with unpaired electrons called free radicals
steal electrons from nearby molecules. 
These stressors cause two intracellular proteins, Bax and Bak, to move from
the cytosol to the mitochondria. 
Once in the mitochondria, Bax and Bak pierce the outer mitochondrial
membrane making it porous and leaky. 
This allows two additional proteins, called SMACS and cytochrome C, to spill into
the cytosol. 
SMACS binds to proteins that normally inhibit apoptosis and deactivates them. 
Meanwhile, cytochrome C binds to both ATP - the main form of intracellular energy -
as well an enzyme called Apaf-1. 
Together, cytochrome C and Apaf-1 combine to form a large protein complex called
an apoptosome. 
The Apaf-1 portion of the apoptosome then cleaves an enzyme called pro-caspase 9
into its active form, caspase-9. 
Caspase 9 then goes on to activate caspase-3, and caspase-3 goes on to activate
other caspases - like a chain event. 
Eventually this caspase cascade leads a cell to commit apoptosis. 
That’s because these caspases cleave the proteins that make up the cell’s
nucleus, organelles, and cytoskeleton - a bit like a ninja sabotaging a bridge by
removing its nutsand bolts.
This destroys the cytoskeleton, as well as the proteins that anchor
the cytoskeleton to the cell membrane. 
As a result, the cell membrane starts to develop blebs - or bulges in the cell
membrane. 
The blebs are structurally weak, so they start to break off from the cell membrane,
and this attracts nearby macrophages, which begin to clean up the mess by eating
up the cell fragments. 
So apoptosis is a neat process that conveniently recycles the organic contents of the
dead cell. 
Now, when the signals from apoptosis come from outside the cell - it’s called
the extrinsic pathway. 
One example is when a nearby macrophage recognizes an old cell,
a pathogenic cell, or a cell that has completed its task. 
In these situations, a macrophage can initiate apoptosis by releasing tumor necrosis
factor alpha or TNF-alpha, a cell signaling protein, that binds to very appropriately
named death receptors on the target cell membrane, one example being tumor
necrosis factor receptor1. 
The cytosolic end of this receptor, dives deep inside the cell, and it’s called the death
domain.
When the TNF-alpha binds to the tumor necrosis factor receptor 1, the death
domainchanges its shape and is able to bind to two proteins. 
One is called Fas-associated protein with death domain or FADD and the other is
called take a deep breath here Tumor necrosis factor receptor type 1-
associated DEATH domainprotein or TRADD. 
So the death receptor, FADD, and TRADD come together to form a multi-complex
protein called... wait for it... the death-inducing signaling complex or DISC.
Once everything is together, DISC cleaves pro-caspase-8 into caspase-8, which in
turn activates caspase-3, and caspase-3 goes on to activate other caspases. 
This initiates the caspase cascade that commits the cell to apoptosis. 
After that, the process of apoptosis unfolds just like in the intrinsic pathway.
Now in addition to macrophages, if a cytotoxic T cell detects that a cell is expressing
foreign antigens, the T cell will express a protein on its membrane called Fas
ligand which binds to a death receptor on the target cell called the first apoptosis
signal receptor - or Fas receptor. 
Similar to the death domain of tumor necrosis factor receptor 1, the Fas
receptor protein also has its very own death domain that can bind to FADD to
form DISC. 
As before, DISC activates pro-caspase-8 into caspase-8 and that triggers
the caspase cascade which leads to apoptosis.
Now let’s switch gears and look at necrosis - which can be triggered by external
factors like an infection or extremely hot or cold temperatures, as well as internal
factors like tissue ischemia. 
Necrosis can start one of two ways. The first is a form is called oncosis, which starts
when toxins or ischemia damage the mitochondria. 
If the mitochondria no longer synthesize ATP, everything stops working - including
the ionic pumps that regulate the flow of ions in and out of the cell. 
Without functioning ion pumps, sodium starts to flow into the cell and its followed by
water which causes the cell to swell up like a balloon. 
Soon, the cell bursts and spills its internal contents on neighboring cells, and this
attracts nearby immune cells and triggers the inflammatory process. 
Immune cells release substances like proteases, which are enzymes that degrades
proteins, and reactive oxygen species - which are unstable and damage other cells. 
If this inflammatory process occurs among enough cells, it can destroy the tissue,
and if it happens on a massive level it can lead to organ dysfunction. 
Now it turns out that cell necrosis comes in a few different flavors. 
First, there’s coagulative necrosis, which occurs when a tissue becomes hypoxic -
has low levels of oxygen - most commonly due to ischemia. 
Hypoxia causes structural proteins to bend out of shape - like twisting a paperclip so
that it can no longer work. 
Hypoxia also affects lysosomal enzymes which become ineffective at getting rid of
the affected proteins.
So although the cells die, they retain some structure and don’t get completely
destroyed. 
From a macroscopic level, the dead tissue becomes a gel-like substance, and has a
pale wedge-shape, with the apex oriented towards the obstruction. 
That’s because a blood vessel typically serves a region of tissue that typically fans
out, and all of that tissue becomes hypoxic and then undergoes coagulative
necrosis.
Occasionally, blood re-enters the area of necrosed tissue, like if a blocked blood
vessel opens back up - and when that happens it gives the tissue a dark
red color and it’s called a red infarct. 
Coagulative necrosis can occur in any cell of the body, but it occurs most often when
there’s low oxygen to heart, kidney, or spleen tissue.
Next, there’s liquefactive necrosis, and that occurs when hydrolytic
enzymes completely digest the dead cells into a creamy substance full of
dead immune cells - think of a cream filled donut. 
Liquefactive necrosis is most commonly seen in the brain, however, it can also
happen to pancreatic cells, or within an abscess located anywhere in the body. 
The brain has resident macrophages called microglial cells that contain hydrolytic
enzymes. 
These enzymes completely destroy damaged brain cells - basically liquefying the
dead brain tissue. 
Similarly, the pancreas has various enzymes like trypsin that are designed
to digest food, but sometimes get activated in chronic inflammation due
to gallstones or alcohol consumption, and destroy the pancreatic tissue itself. 
Finally, in abscesses, neutrophils use their proteolytic enzymes to liquify tissue -
which results in pus. 
Next, there’s gangrenous necrosis, and it also occurs due to hypoxia - so, that’s why
some consider it a form of coagulative necrosis. 
Gangrenous necrosis typically affects the lower limbs and gastrointestinal tract, and
it causes the tissue to get dried up like a mummy - sometimes called dry gangrene. 
But if the dry gangrene gets infected, then liquefactive necrosis can occur, and then
it’s called wet gangrene.
Next, there’s caseous necrosis, and it’s a bit of a mix between coagulative
and liquefactive necrosis. 
Typically, it’s the result of a fungal or mycobacterial infection -
classically Mycobacterium tuberculosis which causes tuberculosis. 
The dead cells disintegrate but are not fully digested, which leaves the tissue with a
cottage cheese consistency. 
Next, there’s fat necrosis, which most commonly occurs when there’s trauma to fatty
organs that have a lot of adipose cells, like the pancreas or the breasts. 
Trauma to the pancreas or the breasts ruptures the adipose cell membranes, which
makes them spill their fatty acids into the extracellular space. 
There, the fatty acids combine with calcium, which leads to dystrophic calcifications
in the tissue -that look like bits of chalk in the tissue.
Now, in addition, the pancreas can also undergo fat necrosis as a result of
inflammation - called pancreatitis. 
With pancreatitis, the pancreatic cells spill lipase around the pancreas. 
Lipase helps digest fats, so it causes fatty acids to spill out of the
fatty retroperitonealtissue that’s adjacent to the pancreas. 
Finally, there’s fibrinoid necrosis which is almost always found in malignant
hypertensionand vasculitis. 
With hypertension, a constant high blood pressure damages the muscular wall of the
small arteries, so fibrin - a protein involved in the clotting of blood - starts
to infiltrate and damage the walls of the damaged blood vessels. 
Similarly, in vasculitis, there’s an inflammatory reaction in the blood vessel walls that
causes destruction. 

Summary
Alright, as a quick recap, apoptosis is a commonly occurring form of programmed
cell death, whereas necrosis is a less common process where cells die due to injury
or disease. 
Apoptosis occurs due to intrinsic and extrinsic pathways. 
With apoptosis, white blood cells come in and clean up the dead tissue, so this is a
neat way for cells to die. 
Necrosis occurs because of external factors like an infection, as well as internal
factors like tissue ischemia.
There’s six types of necrosis: coagulative and gangrenous necrosis, which happen
to hypoxic tissues; liquefactive necrosis, which happens because of hydrolytic
enzymes; caseous necrosis - like in tuberculosis; fat necrosis, which happens
when fatty acids spill outside adipose cells, like during trauma, and finally fibrinoid
necrosis - which is caused by fibrin deposits, like in malignant hypertension.

Athropy,aplasia,hypoplasia
Growing is an important part of living. 
In fact, everything from an individual muscle cell, to a baby blue whale - strives to
grow, in order to live and perhaps replicate or reproduce. 
Sometimes, however, growth fails to occur, or even reverts back, and we call that
atrophy, aplasia, or hypoplasia, depending on the situation. 
Let's break down these words. Atrophy, “a” means “no”, and “trophy”,
means nourishment. So, atrophy means “no nourishment”. 
Aplasia, “a” means “no” and “plasia” means development. So aplasia means “no
development”, and “hypo” means “under” so hypoplasia is “under formation”. 
In a nutshell, atrophy is the reduction in size of a cell, organ, or tissue, after it has
attained its normal, matured growth.
This happens either through decrease in cell number or decrease in cell size. 
Decrease in cell number most commonly happens due to apoptosis, which is
controlled type of cell death - a bit like cellular suicide. 
An example would be weight loss. In the first few weeks to months of eating healthy
and losing weight, the fat cells or adipocytes get smaller but are ready to fill up again
with fat.
Over months to years of eating healthy, however, the adipocytes undergo apoptosis
- and at that point it’s a bit more difficult to gain back the weight. 
Decrease in cell size, however, is a bit more complex.
Usually, the first step is the loss of nerve or hormonal supply, both of which
provide nourishment to cells. 
Then there’s something called the ubiquitin proteasome pathway.
You see, cells have a cytoskeleton, which is a framework of various filaments that
keep the cell propped up. 
As cells start getting less nourishment, those filaments get “tagged” for demolition
with a protein called ubiquitin. 
Ubiquitin proteins start to attach to one another - a process known as
polyubiquitination. 
And then an intracellular protein complex called a proteasome comes in to destroy
all polyubiquitinated filaments, causing the cell to decrease in size. 
Some organelles can also be tagged with ubiquitin; and when that happens, a
bubble of phospholipid bilayer membrane forms around the organelle, creating
a vacuole. 
Next, lysosomal vesicles which are filled with degradative enzymes, fuse with
the vacuole; destroying the unfortunate organelle. Like being sent off to the firing
squad.
An example is muscle atrophy. 
Anytime there’s long-standing disuse of muscles, like extended bedrest, zero gravity,
or during long study sessions, there can be a loss of muscle mass and strength. 
The good news is that this type of muscle atrophy is reversible with exercise. 
There’s also a more severe form of muscle atrophy which happens in cachexia - or
whole body wasting syndrome. 
That form of muscle atrophy is often so severe that it’s not typically reversible and
happens in severe illnesses like AIDS, or in some forms of cancer patients.
But atrophy is not necessarily pathological - in fact, it’s often a part of normal
development. 
For example, it happens in the thymus. 
The thymus is a small organ that sits over the heart and is responsible for the
maturation of T cells which are part of the immune system. 
As children grow and their immune system gets established, the thymus begins to
atrophy. 
This process is called thymus involution. 
As a result, the thymus is much larger in young children than it is in adults. 
Now, aplasia and hypoplasia are somewhat different; they’re both ways in which
growth can go wrong during embryogenesis - when our organs develop within the
fetus. 
With aplasia, the precursor cells are completely absent, while in hypoplasia, there
are some precursor cells present, but not enough of them. 
With aplasia, the organ never forms in the first place- so this is the more severe
case. 
Going back to the thymus again. In DiGeorge syndrome, a small part of the 22nd
chromosome is deleted, so the genes that code for the thymus are gone. 
As a result the cells never have the DNA they need to express the proteins that
would turn them into thymic precursor cells.
As a result, the thymus never forms, and the person is left with a severely
impaired immune system.
Hypoplasia, or underdevelopment, is more common and usually results in milder
consequences. 
Here there are only some precursor cells available, and that results in a smaller, or
misshapen organ.
One example is a genetic disease called optic nerve hypoplasia, where there are
fewer neurons than normal serving the eye.
As a result, the optic nerve is abnormally thin. The result can vary wildly - from
near blindness, to near normal eyesight, all depending on how many axons formed
in the first place.

Summary
Alright, as a quick recap - atrophy, aplasia, and hypoplasia are terms for lack or
absence of growth in an organ or a tissue. 
Atrophy means the wasting of a previously normally mature organ or
tissue, aplasiausually means a complete congenital lack of an organ or a tissue,
while hypoplasia means a relative congenital lack of cells in an organ or a tissue.
Metaplasia and dysplasia
Do you remember your first day in elementary school? Everything and everyone was
new and nothing was impossible. 
But as you went through your education, you got further and
further differentiated from your original classmates. 
That's analogous to what happens to a cell that undergoes cellular differentiation. 
An undifferentiated stem cell can become pretty much any tissue, influenced by both
genes and the environment.
Now sometimes, environmental stresses can alter that developmental path. 
In metaplasia what happens is that a mature, differentiated cell type is replaced by
another mature, differentiated cell type. 
Often, this happens because there’s an environmental stressor, that the new cell
type is better suited to handle. 
One example, is switching from breathing clean air to inhaling tobacco smoke each
day.
Our airways are lined with columnar respiratory epithelial cells, which generally work
well with air breathing, but not so well when faced with an irritant, such as tobacco
smoke. 
In response to the toxins in the smoke, already differentiated, mature columnar
respiratory epithelial cells are replaced by stem cells undergoing differentiation into
sandbag-shaped squamous epithelial cells, which become stratified - meaning that
they form layers on top of another. 
This replacement of already differentiated, mature cells into another type of cell is
known as metaplasia. 
Another example is our esophagus, which is lined with a nonkeratinizing squamous
epithelium. 
These cells are adapted to withstand the passage of food going down to our
stomach. 
However, in case of gastroesophageal reflux disease, acid from the stomach makes
its way up into the esophagus on a regular basis. 
Esophagus cells are not well-suited for chronic contact with acid and can get
damaged. 
Normally, when there’s occasional damage, stem cells differentiate into
new squamous epithelial cells to replace the damaged ones. 
But when there’s regular exposure to acid, stem cells begin to adapt by
differentiating into nonciliated, mucin producing columnar epithelial cells. 
These cells are far better suited to withstand the acid - after all, they’re the
same types of cells that are found in the small intestine. 
This is an example of metaplasia, and the condition is known as
Barrett’s esophagus. 
Now, metaplasia is technically reversible - so if the gastroesophageal reflux
disease is treated, stem cells will begin to divide into regular esophagus epithelial
cells again. 
On the other hand, if the problem persists, the cells can become dysplastic.
In dysplasia, the tissue develops a large number of immature cells that have weird
shapes, which you don’t typically expect in normal, healthy tissue. 
There are four major pathological microscopic changes. 
The first is cellular pleomorphism meaning that the cells are of uneven size - which is
a strange finding, since usually tissue contains cells that are of roughly the same
size. 
Next there’s nuclear pleomorphism or variation in size and shape of the nucleus. 
There’s also hyperchromatism - which means that the cells have abnormal nuclear
morphology due to abundant nuclear chromatin, resulting in darkly staining nuclei. 
And finally, there can be an increased number of cells with mitotic figures - meaning
that a lot of cells are undergoing mitosis, or cell division. 
All of these are signs of unhealthy cells that may be cancerous. 
Let’s take the example of the cervix, which is normally lined with glandular
epithelium. 
However, infection with certain strains of human papillomavirus, or HPV, can cause
the cells to become dysplastic. 
They can resemble immature squamous, epithelial cells, of various sizes and
shapes, and they multiply at a faster rate than normal cells would. 
Uncontrolled multiplication is generally bad news, therefore, dysplasia is considered
a precancerous state. 
As they multiply further, we begin to speak of carcinoma in situ - which is a localized
cancer. 
Sometimes these immature and abnormal cells start to multiply so much that they
break through the basement membrane. 
The basement membrane is a layer of fibrous tissue that separates epithelial tissue
from underlying tissues. 
So if the cells break through that barrier and continue multiplying, they can begin
exerting pressure on local tissues, and break off clumps of cells that can go off to
other tissues to spread the problem. 
At this point it’s considered an invasive, cervical carcinoma. 

Summary
Alright, as a quick recap. Metaplasia and dysplasia typically result from
chronic environmental stressors. 
Metaplasia is the replacement of one mature type of cells into another mature type of
cells, while dysplasia is an increased amount of immature cell types, which may
sometimes show unusual properties as well. 
Metaplasia is generally benign, while dysplasia is considered a precancerous state,
that can develop into carcinoma.
Hyperplasia and hyperthrophy
Imagine a lumberjack. At first she can handle cutting down a few trees a day, but
suddenly her boss wants her to chop down an entire forest by the end of the week!
Now she's stressed out from the increased demand! 
Our body is the same; when the demand placed on an organ or tissue is more than it
can handle, its called “stress,” and the body can adapt through either hyperplasia or
hypertrophy. 
Hyperplasia refers to the process where cells in an organ or tissue increase in
number, so its like hiring a bigger pack of lumberjacks. 
Hypertrophy is when these cells in an organ or tissue increase in size, like if the
lumberjack gets really tough so that she can cut down twice as many trees. 
So hyperplasia, bigger pack, and hypertrophy, tough lumberjack!
So, a tissue or organ might get stressed by physiological processes or from disease
processes. 
An example of physiologic hypertrophy is lifting a 10 pound sack of potatoes which
puts a bigger functional demand on your skeletal muscles. 
In response, the muscle cells produce more proteins or myofilaments and get larger
in size, allowing the biceps as a whole to generate more force. As a result your
muscles also become bigger and tougher. 
An example of pathologic hypertrophy is when the heart undergoes hypertrophy to
deal with high blood pressure or hypertension. 
In hypertension, the heart has to pump blood against a high resistance and cardiac
myocytes once again adapt by increasing the synthesis of myofilaments causing
individual cells to get bigger. 
In both cases there’s hypertrophy, but the triggers are quite different.
Now, in hyperplasia there’s an increase in the number of cells - a larger pack. 
And that can only happen in organs with stem cells that can undergo cellular
differentiation to become a mature cell in that organ, like cells in the intestines for
example. 
So hyperplasia doesn’t occur in relatively permanent tissues without stem cells- like
cardiac, nerve, and adult skeletal muscle tissue. 
And that’s why those tissues typically only undergo hypertrophy when they face
increased stress. 
Now there’s compensatory hyperplasia and hormonal hyperplasia. 
Compensatory hyperplasia occurs in organs that regenerate, like the skin, lining of
the intestines, the liver, and bone marrow. 
Hormonal hyperplasia occurs in organs that are regulated by hormones like organs
in the endocrine and reproductive system. 
Like hypertrophy, hyperplasia can also be physiological or pathological. 
An example of physiologic hyperplasia is enlargement of the female breast during
pregnancy. 
In preparation for breastfeeding, hormones like prolactin, progesterone, and human
placental lactogen stimulate the growth of glandular tissue in the breast causing
them to enlarge.
An example of pathologic hyperplasia is having excessive hormonal stimulation. 
For example, normally, during a menstrual cycle, the endometrium, which forms the
inner lining of the uterus, grows and proliferates when exposed to estrogen. 
But if there is an overproduction of estrogen by an ovarian tumor, it can lead to
excessive endometrial growth - also called endometrial hyperplasia.
Now, one problem with hyperplasia is that it’s sometimes associated with cancer.
Normally, hyperplasia is an adaptive response to stress, so it’s a tightly regulated
process, meaning the tissue doesn’t grow out of control. 
And in hyperplasia the process stops if the stress factors are eliminated.
That’s different from cancer where there’s uncontrolled cell division. 
Now, the thing is that as cells divide in hyperplasia some can mutate and that’s how
hyperplasia can slip into dysplasia and eventually into malignancy. 
While cells from hyperplasia are normal and healthy, cells from dysplasia can have
an abnormal shape and function. 
And malignant cells might not only be abnormal, but also replicate uncontrollably,
causing cancer. 
And that’s why individuals with endometrial hyperplasia that’s left untreated, can
develop endometrial cancer. 
Finally, it’s important to remember that in tissues that have stem cells, hyperplasia
and hypertrophy usually occur together when there’s increased stress. 
For example, in pregnancy, the uterus gets stimulated by estrogen, which lead to
hypertrophy and hyperplasia of the smooth muscle cells in the uterine wall. Meaning
that the cells get tougher and the pack of cells gets more numerous.

Summary
Alright, as a quick recap, whenever an organ encounters any sort of physiological or
pathological stress, it adapts by hyperplasia or hypertrophy. 
You can remember that as - hyperplasia, bigger pack, and hypertrophy, tough
lumberjack! 
In general, hyperplasia and hypertrophy occur together in organs with stem cells like
the skin, liver, bone marrow or uterus. 
Organs that lack stem cell like the heart, skeletal muscle, and nerve can only
undergo hypertrophy.
Oncogenes and tumor suppressor genes
Oncogenes and tumor suppressor genes are classes of genes that code for various
proteins that are involved in the progression of the cell cycle. 
Oncogenes are actually mutated versions of proto-oncogenes, which are normal
genes in charge of positive regulation of the cell-cycle. 
So the protein products of proto-oncogenes stimulate cell growth and division -
they're like a gas pedal in a car.
Tumor suppressor genes, on the other hand, are in charge of negative regulation of
the cell cycle, so their protein products stop its progression and promote apoptosis or
cell death. 
Tumor suppressor genes are involved in DNA repair mechanisms and
inhibiting transcription factors that try to push the cell along in the cell cycle - so
they’re like the brake pedal in a car.
Now, the cell cycle is the series of events that a cell goes through as it changes from
being one cell into two daughter cells. 
The cell cycle has two phases: interphase and mitosis. Interphase is comprised of
the G1 phase, during which the cell grows and performs its cell functions, the S
phase, during which DNA is replicated, and the G2 phase, during which the cell
grows again before entering mitosis. 
At the end of G1 and G2, there are cell cycle control points called the G1 and
G2 checkpoints, where the cell checks to see if there’s any DNA damage.
The main control point is the G1 checkpoint. 
If it turns out that there is DNA damage, then the cell can either enter a non-dividing
state called the G0 phase, where the DNA repair mechanisms try to fix the problem,
or the cell can self-destruct in a process called apoptosis. 
Now, if the cell does get the go-ahead at the G1 checkpoint, it enters the S phase. 
And then if the cell gets past the G2 checkpoint, it enters mitosis, and it divides in
two identical daughter cells. 
However, once cells differentiate and become mature cells - like liver cells for
example - they don’t necessarily go through the cell cycle over and over again. 
Actually, cells tend to stay in that G0 phase, and some cells, like neurons, stay in G0
their entire life.
Most other cells, however, stay in G0 until they get an external signal like a growth
factor. 
These growth factors can be secreted by other cells, or by the cell itself, like when
there’s a tissue injury, and the remaining cells need to divide to replace the lost
cells. 
Growth factors bind to growth factor receptors in the cell’s membrane, which
activates signal transduction proteins.
Ultimately that leads to increased transcription of genes that code for special
proteins - like cyclins and cyclin dependent kinases - so more of these proteins are
being made. 
This is important because whether or not a cell gets cleared at G1 and G2, depends
largely on the activity of cyclin dependent kinases, which add phosphate groups to
various proteins within the cell. 
And these cyclin dependent kinases are, as you might guess, dependent
on cyclinproteins. 
So what happens is that when there’s DNA damage, the cell doesn’t produce cyclins,
the cyclin dependent kinases can’t phosphorylate proteins within the cell, and that’s
the signal for the cell to halt the cell cycle.
Okay, so proto-oncogenes code for proteins involved in promoting the progression of
the cell-cycle.
Examples of proto-oncogenes include genes that code for growth factors or growth
factorreceptors - like the receptor tyrosine kinase or RTK which adds phosphate
groups to other proteins. 
Another example are genes that code for signal transduction proteins -
like Ras genes, that code for Ras proteins. 
Ras proteins are GTP-ases, meaning that they bind an intracellular GTP molecule,
and break it down into GDP and a free phosphate group. 
This further activates various cellular pathways, which ultimately result in cell growth,
differentiation, and survival. 
Another example is the MYC proto-oncogene which codes for a transcription
factor that increases expression of cyclins and cyclin dependent kinases.
On the other hand, there are also proto-oncogenes that code for proteins that inhibit
apoptosis.
An example is bcl-2 which prevents the activation of caspases - the enzymes that
actually carries out apoptosis. 
Now, proto-oncogenes are normally only active when a cell needs to grow and divide
- like you only push the accelerator pedal in a car when you want to speed up. 
However, some genetic mutations like translocations, amplifications, or point
mutationsturn proto-oncogenes into oncogenes.
When a gene is an oncogene it gets overexpressed - meaning, it results in too many
proteins, or it means that it codes for hyperactive proteins - which would be kinda like
leaving a brick on the gas pedal and going to take a nap in the backseat as
the car speeds down the highway. 
Cells have two copies of proto-oncogenes; however, if there’s a dominant mutation,
that means that just one mutant oncogene copy is enough for the cell to avoid
apoptosis and keep growing and dividing uncontrollably. 
One example is a type of B cell lymphoma called Burkitt lymphoma, which can result
from a chromosomal translocation. 
When that happens the Myc gene is translocated from chromosome 8 to a spot
where it’s right next to the IgH promoter on chromosome 14 which upregulates - or
stimulates - its expression. 
The Myc protein then
induces overexpression of cyclins and cyclin dependent kinases - which leads to
uncontrolled cell growth - a lymphoma. 
Other oncogenes can result from a fusion gene. 
For example, the most common cause of chronic myeloid leukemia is a chromosome
translocation which results in a Philadelphia chromosome. 
A Philadelphia chromosome is one where a portion of chromosome 9’s long arm
switches with a portion of chromosome 22’s long arm.
The result is two chromosomes - 9 and 22 - each of which have a bit of one another,
and it’s chromosome 22 with a bit of chromosome 9, that’s called the Philadelphia
chromosome. 
So, in the Philadelphia chromosome, a chromosome 22 gene, called BCR, ends up
sitting right next to a chromosome 9 gene, called ABL. 
When they’re combined it forms a fusion gene called the BCR-ABL gene, which
codes for a protein also called BCR ABL which is always getting expressed. 
Now it turns out that BCR ABL has tyrosine kinase activity, meaning that it works as
an on-off switch for various cellular functions, including cell division. 
Now because the BCR ABL gene is always getting expressed, the result is
that myeloidcells keep dividing. 
This causes a buildup of premature leukocytes in the bone marrow, which eventually
spill into the blood - ultimately leading to leukemia!
Now, let’s switch gears to see how tumor suppressor genes work. Tumor suppressor
genes code for proteins that stop the cell cycle or promote apoptosis - so they’re
the cell cycle’s very own brake pedal.
Like proto-oncogenes, tumor suppressor genes are also normally active throughout
the cell cycle, and they code for proteins that halt its progression if there’s any sort
of DNA damage. 
Some genetic mutations - mainly deletions - turn off the expression of tumor
suppressor genes - which leads to a reduction in the number or function of the
protein that they encode.
This is a recessive kind of mutation, because it takes two damaged copies for tumor
suppressor genes to have no functioning proteins. 
When that happens, it’s relatively easy for genetic mutations to accumulate,
ultimately allowing the cell to keep growing and dividing uncontrollably. 
That’s why a wide variety of cancers feature mutated tumor suppressor genes.
For example, the Rb protein is considered a “governor” protein, because it normally
inhibits cell proliferation by binding and inactivating a transcription factor called E2F. 
Normally, E2F promotes transcription of cyclin E, and cyclin dependent kinase-2, but
it can’t do that with Rb holding on to it for dear life.
But, here’s the catch - the Rb protein is only active and clinging to E2F when it isn’t
bound to a phosphate. 
So when a growth factor stimulates a growth signaling pathway, that activates
the cyclindependent kinases which add a phosphate group to Rb, inhibiting it.
Phosphorylated Rb releases E2F, allowing the cell cycle to progress.
It’s like bribing the inspector with a phosphate to let the cell keep moving ahead with
it’s plans. 
In many types of cancer, including retinoblastoma - which gives Rb its name, Rb is
inactivated and the loss of the brakes increases the rate of cell division. 
Typically, Rb is inactivated by a gene mutation, or by other proteins that specifically
inactivate the Rb protein - like protein E7 made by human papillomavirus. 
Another example, is the p53 “guardian” protein. P53 is a transcription factor that
checks for DNA damage before a cell enters the S phase. 
And if there is DNA damage, then specific protein kinases add phosphate
groups to p53 - prolonging its life.
P53 binds to DNA and promotes transcription of a gene encoding protein called p21.
p21 binds and inhibits the cyclin E-cyclin dependent kinase-2 protein complex, thus
preventing passage from the G1 phase to S phase.
This buys a bit of time for DNA repair proteins, which are also expressed thanks
to p53 - to get to work. 
It turns out that P53 is a big deal in the molecular world, and was actually crowned
“molecule of the year”, back in 1993! 
In fact, studies have found that more than 70% of human cancers are associated
with mutations in the p53 gene. 
When mutations inactivate p53, the cell can no longer repair DNA before it enters
the S phase, which means mutations build up, and this can lead to uncontrolled cell
division.

Summary
Alright, as a quick recap, oncogenes are actually mutated versions of proto-
oncogenes, which are normal genes that act like the accelerator pedal on the cell
cycle - so they stimulate cell growth and division. 
Their protein products are growth factors, growth factor receptors, signal
transductionproteins, transcription factors, and apoptosis regulators.
Tumor suppressor genes are like the brake pedals on the cell cycle - they inhibit
progression to mitosis and/or promote apoptosis.
They include governor and guardian proteins like Rb and p53.

Lung cancer
Lung cancer, or lung carcinoma, is the uncontrolled division of epithelial cells which
line the respiratory tract.
There are two main categories of lung cancer, small cell and non-small cell, which
depend on the type of epithelial cell that's dividing. 
Both types can be fatal, especially if the cancerous cells aggressively spread and
establish secondary sites of cancer in other tissues. 
The major cause of lung cancer is smoking tobacco products, and it has contributed
to the deaths of millions of people including famous individuals like Walt Disney and
Claude Monet.
Air enters the respiratory tract through either the nose or mouth and flows down
the trachea, which divides into the right and left bronchi. 
Each bronchi enters its respective lung at the hilum, or root of the lung. 
The bronchi then divides into lobar bronchi, which divide into segmental bronchi,
then into subsegmental bronchi, which further branch to form
conducting bronchioles and then respiratory bronchioles which end with small, sacs
called alveoli that are surrounded by capillaries, which is where gas
exchange occurs. 
Lining these airways are several types of epithelial cells which serve multiple
functions. 
These include ciliated cells that have hair-like project called cilia that work to sweep
foreign particles and pathogens back to the throat to be swallowed. 
Another type, called goblet cells--which are called that because they look like
goblets--secrete mucin to moisten the airways and trap foreign pathogens. 
There are also basal cells that are thought to be able to differentiate into other cells
in the epithelium, club cells that act to protect the bronchiolar epithelium,
and neuroendocrine cells, that secrete hormones into the blood in response to
neuronal signals. 
Cells can become mutated because of environmental or genetic factors. 
A mutated cell becomes cancerous when it starts to divide uncontrollably. 
As cancer cells start piling up on each other they become a small tumor mass, and
they need to induce blood vessel growth, called angiogenesis, to supply themselves
with energy. 
Malignant tumors are ones that are able to break through the basement membrane. 
Some of these malignant tumors go a step further and detach from their basement
membrane at the primary tumor site, enter nearby blood vessels, and establish
secondary sites of tumor growth throughout the body - a process called metastasis. 
A well known risk factor for small cell lung cancer and some types of non-small cell
lung cancer is smoking tobacco, and it’s dose-dependent which means that smoking
more cigarettes over a longer period of time increases the risk.
Another risk factor is exposure to radon, a colorless, odorless gas which is a natural
breakdown product of uranium found in the soil.
Other environmental factors include asbestos, air pollution, and ionizing radiation,
like from medical imaging with chest X rays and CT scans. 
There are also some gene mutations that are known to be associated with an
increased risk of lung cancer development. 
Once it develops, lung cancer tends to metastasize quickly, rapidly establishing sites
of secondary tumors in other tissues. 
Tissues particularly at risk as a secondary site are the mediastinum and hilar lymph
nodes because of their proximity to the lungs, but other sites include the
lung pleura - the lining of the lungs, heart, breasts, liver, adrenal glands, brain, and
bones.
Lung cancer can be categorized as either small cell or non-small cell carcinomas. 
Small cell carcinomas account for a small portion of lung cancers and originate from
small, immature neuroendocrine cells. 
That means that non-small cell carcinomas account for most lung cancers, and these
can be further subdivided into four categories: adenocarcinomas which frequently
form glandular structures or have the ability to generate mucin; squamous cell
carcinomas; which have squamous, or square shaped, cells that
produce keratin; carcinoid tumors from mature neuroendocrine cells; and large
cell carcinomas which lack both glandular and squamous differentiation.
Small cell carcinoma is strongly associated with smoking and usually
develops centrally in the lung, near a main bronchus. 
In general, they grow the fastest and more rapidly metastasize to other organs than
other types of non-small cell lung cancers. Because of this, by the time it’s
diagnosed, it’s common to find large tumors in multiple locations both within and
outside the lung.
Typically when small cell carcinoma is within one lung, it’s considered limited, if it
spreads beyond one lung it’s considered extensive.
Small cell carcinomas can also sometimes secrete hormones and that can lead to
what is called a paraneoplastic syndrome. 
One example is when the tumor releases adrenocorticotropic hormone causing an
increase in production and release of cortisol from the adrenal glands. This causes
what’s known as Cushing’s syndrome which causes a number of symptoms
including an elevated blood glucose and high blood pressure.
Another example is when the tumor releases antidiuretic hormone which
causes water retention leading to high blood pressure, edema and concentrated
urine. 
A slightly different type of paraneoplastic syndrome, is when small cell
carcinoma prompts the body to produce autoantibodies which bind and destroy
neurons causing Lambert-Eaton myasthenic syndrome, which is a type II
hypersensitivity reaction. 
Non-small cell carcinomas are more of a mixed bag in terms of where they usually
arise. 
Just like small cell carcinoma, squamous cell carcinoma tends to be centrally located
and has a strong association with smoking. 
In contrast, adenocarcinoma tends to develop peripherally, in
a bronchiole or alveolar wall, and doesn’t have a link to smoking.
Large cell carcinomas and bronchial carcinoid tumors can be found throughout the
lungs - centrally and peripherally. 
Of these two, large cell carcinoma is linked to smoking. 
Both adenocarcinoma and squamous cell carcinoma can form Pancoast tumors,
which are masses in the upper region of the lung that compress the blood vessels
and nerves located there. 
In particular, pancoast tumors can compress and damage the thoracic inlet, brachial
plexus, and cervical sympathetic nerves leading to their dysfunction and Horner
syndrome. 
Clinical symptoms of Horner syndrome include a constricted pupil, a drooping upper
eyelid, and loss of ability to sweat on the same side of the body as
the dysfunctionalsympathetic nerve. 
A classic paraneoplastic syndrome associated with squamous cell carcinoma is the
release of parathyroid hormone which depletes calcium from the bones causing
them to become brittle and increasing calcium levels in the blood. 
And, finally, a paraneoplastic syndrome specific to carcinoid tumors is carcinoid
syndromewhich causes the secretion of hormones, particularly serotonin, which
leads to increased peristalsis and diarrhea,
and bronchoconstriction causing asthma. 
Since non-small cell carcinomas tend to be slower growing and slower to spread
than small cell, staging is more elaborate.
It’s called “TNM” staging and represents three diagnostic categories: T, for tumor
size and extent of local extension; N, for spread into nearby lymph nodes in the
chest, particularly the mediastinum and hilar lymph nodes; and M, for metastasis to a
secondary site. 
Within each of these categories are sub-stages, T0-T4, N0-N3, and M0-M1, where
an increasing number means increasing severity. 
Finally, the combinations of these sub-stages determine thes stage group, assigned
0 to IV. 
So for example, if the diameter of the tumor is less than or equal to 3 cm and not in a
main bronchus, has invaded the hilar lymph node on the same side of the chest, but
has not spread outside the chest to other tissues, it’s categorized as T1, N1, M0 and
can be considered stage group II. 
But if the tumor metastasizes to a secondary site, it's considered M1
and staging group IV regardless of it's T or N value. 
Symptoms of lung cancer vary based on the size and location of the tumor, whether
or not is has spread to other organs, and whether or not it generates hormones - all
of which is often predicted by the type of cancer. 
In response to the cancer cells, the body mounts an immune response which results
in the release of chemokines like TNF-alpha, IL1-beta, and IL-6 which can cause
weight loss, fevers, and night sweats. 
If the primary tumor physically obstructs the airway and presses on surrounding
tissue structures it can cause a cough, shortness of breath, and leads to
a pneumonia in the lung tissue behind the obstruction. 
Compression of nearby nerves can cause pain, and compression of specific nerves
like the recurrent laryngeal nerve and phrenic nerves can cause changes in voice
or difficulty breathing, respectively. 
Compression of nearby vessels like the superior vena cava can cause a backup of
blood in the face leading to facial swelling and shortness of breath. 
Finally, if a cancer cells invade into a blood vessel then mucus can get blood tinged
or blood clots can get coughed up.
Initially lung cancer is usually identified as a coin-shaped spot, called a coin lesion
on chest X-ray, or a non calcified nodule on chest CT. 
Infections can also cause similar shaped spots, so a tissue biopsy from a
bronchoscopy or a CT-guided fine-needle aspiration is typically done to make
a histopathologic diagnosis. 
Though treatment will vary by category and stage of the lung cancer, often a
commonality is the use of surgery if appropriate, chemotherapy or immunotherapy,
and radiation therapy when possible. 
In general, the goal of surgery is to remove as much of a tumor, ideally all of it, and
to have a small border of healthy tissue around it so that all of the cancerous cells
are gone. 
Depending on the size and location of the tumor, a small wedge of tissue may be
taken, or up to an entire lung, in which case the airway is sutured shut to prevent air
from leaking into the body cavity. 
In addition, it’s typical to remove nearby lymph nodes which have metastasis and
manage clinical symptoms. 
Since pain is a significant chronic symptom of lung cancer, it’s often managed
through both nonpharmacologic approaches like yoga and guided imagery as well
as pain medications.

Summary
So, a quick recap: Lung cancer is the uncontrolled growth of respiratory epithelial
cells. 
The minority are small cell cancers and the majority are non-small cell, which are
further categorized into adenocarcinoma, squamous cell carcinoma,
bronchial carcinoid, and large cell carcinoma. 
Some common issues for all lung cancers is that they can cause airway obstruction,
compression of nearby nerves and the superior vena cava, cause paraneoplastic
syndromes, and induce an immune response which causes symptoms like weight
loss, fevers, and night sweats. 
Overall, lung cancers have a high rate of metastasis to other organs, and are treated
with a combination of surgery, chemotherapy, immunotherapy, and radiation
depending on the situation.
Pancreatic carcinoma
Pancreatic carcinoma describes the pancreas having cancerous cells arise. 
Now a healthy pancreas has two types of glands, exocrine glands which
sends digestive enzymes off to the small intestine, and endocrine glands which help
regulate metabolism in the body, for example, maintaining normal blood sugar. 
Over 95% of pancreatic tumors develop in the pancreas's exocrine tissues, and of
these, tumors arising in the epithelial cells lining the pancreatic ducts account for the
vast majority of cases.
This type of pancreatic cancer is known as pancreatic adenocarcinoma due to the
cells glandular-like (“adeno”) appearance under the microscope, often pancreatic
adenocarcinoma is used interchangeably with pancreatic carcinoma. 
These tumors typically form in the head or neck of the pancreas, but in some cases
tumors form in the tail. 
Around 5% of exocrine pancreatic carcinomas are caused by malignancies in
the acinar cells, which are the cells that produce the digestive
enzymes like trypsinogen, and around 1% are cystadenocarcinomas, or malignant
cysts. 
There are also other types of pancreatic cancer, but those are even more rare. 
Generally, pancreatic carcinoma is caused by genetic mutations in the ductal
epithelial cells, and these mutations might activate oncogenes which promote cancer
or inactivate tumor suppressor genes. 
Either way, this can lead to uncontrolled cell growth caused by the disruptions of the
cell signalling pathways that regulate cell survival and growth, as well as
multiple immune system responses like inflammation and stress responses. 
Although it’s not exactly clear how the genetic mutations that trigger pancreatic
carcinomadevelop, there are some well known modifiable risk factors like smoking
which increases the risk by two to five-fold, obesity, as well as eating a diet high in
red meat. 
There are also some non-modifiable risk factors like being male, being African
American, and being over 65 years old.
Also, certain other diseases seem to increase the risk of developing pancreatic
carcinomaas well, like diabetes, chronic pancreatitis, and liver cirrhosis, all of which
are linked to excessive alcohol consumption, so there does seem to be an indirect
relationship between pancreatic carcinoma and alcohol as well. 
Finally, a family history of pancreatic cancer is also an important risk factor that
increases individual risk, with inherited mutations in BRCA2, or breast cancer gene 2
being the most common cause of inherited pancreatic carcinoma, and mutations in
PALB2 taking second place. 
Initially symptoms are often vague, like nausea, vomiting, and fatigue. 
There might also be weight loss, which may be due to cancer-associated anorexia,
or malabsorption due to an obstructed pancreatic duct which can cause steatorrhea,
foul-smelling greasy loose stools. 
One of the most specific symptoms of pancreatic carcinoma is midepigastric pain
that radiates to the mid- or lower-back, which often hurts the most at night when the
individual is lying down flat. 
Other classic symptoms that have been described include Trousseau sign, which is
when blood clots, that can be felt as small lumps under the skin, appear
unexpectedly in superficial veins, and then over time, migrate to different locations. 
As well as Courvoisier sign, which is when the gallbladder is enlarged and palpable,
and the patient does not find it at all tender to the touch, which is unlike gallstones.
This occurs when the common bile duct is blocked by a tumor so this sign suggests
the tumor is more likely in the head of the pancreas than the tail. 
The location of the tumor can affect the symptoms as well. 
For example, if the tumor is in the head of the pancreas, then it can block
the common bile duct, leading to a backup bile and causing obstructive jaundice. 
Individuals might have a loss of appetite, darker urine, and lighter stools, as well as
eventually developing pruritus, or itchy skin, and having their skin turn yellow. 
If the tumor affects the endocrine function of the pancreas, then a new onset
of diabetesin an older patient might also be a sign of pancreatic carcinoma. 
Laboratory findings are generally non-specific for pancreatic carcinoma;
serum amylaseand lipase levels may be elevated, as well as tumor markers CA 19-9
antigen, which is a molecule that helps with immune-surveillance, and CEA,
a glycoprotein involved in cell adhesion. 
The activation of oncogenes and tumor suppressor genes can disrupt their
production, so that elevated levels appear in the bloodstream. Since these aren’t
specific for pancreatic carcinoma, though, they might even be elevated in patients
without cancer, particularly those who smoke, and so these can’t be used for
diagnosis. 
Sometimes when there are related problems like obstructive jaundice it might cause
elevated bilirubin, alkaline phosphatase, and transaminase levels. 
Medical imaging techniques and biopsy are used to confirm a diagnosis. 
Staging of the tumor is dependent on size and locations of the tumor. 
Stage 1 is tumors less than 2 cm, stage two is tumors greater than 2 cm, stage 3 is it
can spread to neighboring tissues and organs like the duodenum and the stomach,
and stage 4 is metastatic, meaning it can spread through the blood and lymph to
other tissues like the liver and lungs. 
Finally, imaging can be used to help determine if it’s resectable. 
For treatment, chemotherapy might be given as a neoadjuvant, meaning used to
shrink the tumor before surgery, or as an adjuvant therapy after surgery, or to help
individuals who can’t have surgery at all. 
A major surgical procedure, called a Whipple procedure, is sometimes used to
remove cancer from the head of the pancreas. 
Since several organs share a blood supply in this region of the body it also
necessitates the removal of the gallbladder, the duodenum, and parts of
the jejunum and stomach. 
Unfortunately, most people with pancreatic carcinoma have a poor prognosis
because it’s typically pretty advanced at the time of diagnosis. 
Even among patients with stage I pancreatic carcinoma, the long-term survival rates
are pretty low. 

Summary
Alright, as a quick recap, pancreatic carcinoma is most commonly a cancer of
the exocrine pancreas, especially in the ductal epithelial cells of the head or neck of
the pancreas, and it’s often caused by mutations in oncogenes and tumor
suppressor genes, which leads to unchecked cell growth.
Cervical cancer
Cervical cancer arises in the cervix, most frequently at the transformation zone -
which is where the glandular epithelium of the endocervix meets the squamous
epithelium of the exocervix. 
The most frequent type of cervical cancer is squamous carcinoma, and it's almost
always due to human papillomavirus, or HPV.
HPV strains 16 and 18 account for most cases, and strains 31, 33, 45, 52, and 58
account for the rest. 
However, it can take up to two decades for HPV infection to progress
through precancerous lesions of increasing severity, and finally to cancer. 
So there are two key elements that make cervical cancer unique among cancers. 
First, vaccinating against high risk HPV strains can help prevent cervical cancer. 
Second, a pap smear can be done to screen for precancerous lesions. 
And if they’re found, it’s possible to remove the precancerous lesions before they
progress to cancer.
As a result, cervical cancer is one of the most
preventable gynecologic malignancies. 
Cervical cancer screening is the cornerstone of prevention, and should be done in
both vaccinated and unvaccinated females between the ages of 21 to 65, with
regular pap tests. 
With the pap test, a thin, long brush is used to scrape cervical cells off the cervix. 
The test takes about 2 minutes, but it can cause slight discomfort as well as light
spotting may occur afterwards. 
A normal pap test is when microscopy shows no cervical cell abnormalities. And
when that’s the result, screening can be repeated in 3 years. 
Cervical cell abnormalities can show up as either atypical squamous cells, or ASC or
cervical squamous intraepithelial lesions, or CSIL. 
Atypical squamous cells look mildly atypical, and don’t necessarily develop
into cervical cancer, whereas cervical squamous intraepithelial lesions are full-
blown dysplastic, and have a greater chance of becoming cervical cancer.
ASC results can further be classified as either ASC-US, where US stands for
unknown significance, and there are no high grade intraepithelial lesions, or ASC-H,
which is when there may be a high grade intraepithelial lesion and further testing is
recommended. 
Cervical squamous intraepithelial lesions can be either low grade squamous
intraepithelial lesions, or LSIL, or high grade squamous intraepithelial lesions, or
HSIL, depending on how dysplastic the cells look. 
Management of abnormal pap smear findings depends on the age of the individual.
In females 25 or older, an ASC-US or LSIL result warrants a reflex HPV test. 
That’s where a sample of fluid from the pap test is used to look for HPV DNA. If this
test comes back negative, the female should get another pap smear and HPV test in
3 years. 
On the other hand, if the initial reflex HPV test comes back positive,
a colposcopy should be done. 
Alternatively, instead of doing the reflex HPV test from the get-go, the pap test can
be repeated in one year, and if it comes back negative, the female can go back to
routine screening. 
If the pap test at 12 months shows any kind of abnormality, a colposcopy should be
done. 
Now, a colposcopy is done with a magnifying device called a colposcope to get a
zoomed in view of the cervix as well as to obtain biopsies. 
To better highlight abnormal cells, different solutions, like 3 to 5% acetic acid, or
dilute Lugol solution may be applied, which will cause abnormal cells to
change color.
During colposcopy, biopsies should be obtained from the transformation zone, and
from any other suspicious-looking areas - like those that become white after acetic
acid staining. 
The biopsy is examined under a microscope to look for cervical intraepithelial
neoplasia - or CIN for short, which comes in 3 grades. 
With CIN 1, there are abnormal looking cells only in the deep third of the epithelium.
With CIN 2, the abnormal cells make up approximately two thirds of the epithelium,
and with CIN 3, abnormal cells make up more than two thirds of the epithelium.
Finally, the biopsy can come back either as carcinoma in situ, which is when the
entire epithelium is made up of abnormal cells, but they don’t make it past the
basement membrane, or invasive cervical cancer, when the abnormal cells have
made it past the basement membrane.
Now, if the colposcopy shows no CIN, or CIN1, options include follow-up without
treatment or a diagnostic excisional procedure.
For follow-up, another pap smear and an HPV test should be done in 12 months. If
both of those come back negative, another pap smear and HPV test should be done
in three years. And if both are negative again, the individual can go back to routine
testing. If any tests come back abnormal during follow-up, the colposcopy should be
repeated. 
If CIN1 persists for more than 2 years, a diagnostic excisional procedure can be
done. 
Diagnostic excisional procedures include loop electrosurgical excision procedure,
which is when a wire loop heated with electrical current is used to remove
suspicious-looking cervical tissue, and cold knife conization, which is when a cone-
shaped section of cervical tissue that contains the abnormal cells is removed. 
These come with the downside that they may cause cervical incompetence in future
pregnancies - which means that the cervix doesn’t stay shut like it normally would, to
seal the uterine cavity. 
If the biopsy results come back as CIN 2 or CIN 3, treatment can be done through
loop electrosurgical excision, laser excision or laser ablation of the cervical
transformation zone. 
Then, follow-up involves a pap smear and a reflex HPV test at 12 and 24 months,
and after 2 normal results, the female can go back to routine testing, every 3 years. 
If any test comes back abnormal during follow-up, a colposcopy should be done, as
well as endocervical sampling - which is when biopsies are taken from the
endocervical canal. 
Now, after an abnormal pap smear with an ASC-H or HSIL result in females 25 or
older usually warrants a colposcopy or diagnostic excisional procedures. 
If the colposcopy shows CIN 1, options include repeating the pap smear and HPV
test at 12 and 24 months, and if both tests come back negative both times, the
female can go back to routine screening. 
If any test comes back abnormal at least once during this follow-up,
a colposcopy should be performed. And, in particular, if any pap test during follow-up
shows an HSIL result again, a diagnostic excisional procedure should be done.
Alternatively, a diagnostic excisional procedure may be done from the start. 
If the colposcopy done for an ASC-H or HSIL result shows CIN 2 or CIN 3,
electrosurgical excision, laser excision or laser ablation of the cervical transformation
zone can be done. 
Ok, now in females aged 21 to 24 things are handled slightly differently. That’s
because in young females, an ASC-US or LSIL result doesn’t necessarily mean HPV
infection, or high risk of cervical cancer. 
And even if there is an HPV infection, the immune system may clear it, and these
abnormalities may go away on their own within 24 months. 
So, for an ASC-US or LSIL result in young females, the recommendation is to repeat
the pap test in 12 months instead of 3 years. If the second pap test comes back
negative, or shows ASC-US or LSIL again, a third pap test should be done another
12 months later - so 24 months later than the first abnormal result. 
If the third test comes back negative, repeat a fourth pap test again in twelve months
- and once two tests in a row come back normal, the female can go back to routine
screening, once every three years. 
Alternatively, for ASC-US results, a reflex HPV test can be done. If reflex HPV
testing shows no HPV, the female can go back to routine screening, once every
three years. 
With a positive reflex HPV test, management is still to perform a second pap test in
12 months instead of 3 years, with a goal of getting two consecutive normal results
at 12 month intervals. 
Ok, now, still in the 21 to 24 age group; if the initial pap test, or the second pap test -
the one done after 12 months - comes back as ASC-H or HSIL, or if the third pap
test - the one at 24 months - shows any kind of abnormal result, including ASC-US,
a colposcopy is recommended. 
If the colposcopy shows no CIN, or CIN 1, follow-up involves getting a pap
smear and colposcopy every 6 months for the next two years. 
If two pap smears come back negative for cell abnormalities, and there is still no CIN
2 or CIN 3 on colposcopy, then the female can go back to routine screening, with
pap tests once every three years. 
If the pap test comes back as HSIL, or the colposcopy results show CIN 2 or 3 for
one year, treatment should be done, either through loop electrosurgical excision,
laser excision or laser ablation of the cervical transformation zone. 
If, on the other hand, the colposcopy comes back as CIN 2 or CIN 3 from the start,
both observation and immediate treatment can be options. 
Usually, observation is preferred for CIN 2, and it involves getting a pap smear and
a colposcopy every 6 months for 12 months. 
If both tests are negative both times, a pap smear and an HPV test should be done
12 months later. If that test comes back negative, it can be repeated 3 years later,
and if it’s once again negative, the female can go back to routine screening.
If either the pap smear or the HPV test done at 2 years or 5 year comes back
abnormal, another colposcopy should be done. 
Treatment, on the other hand, is preferred for CIN 2 lasting more than 24 months,
and CIN 3 from the start, and it can be done either through loop
electrosurgical excision, laser excisionor laser ablation of the cervical transformation
zone.
Generally speaking, with appropriate screening, cervical intraepithelial neoplasia can
be caught and removed before it even becomes cervical cancer! If it’s not caught
early, however, cervical cancer can progress without any symptoms for a long period
of time. 
Eventually, symptoms can appear like irregular vaginal bleeding or postcoital
bleeding.
On a pelvic examination, there may be a lesion suggestive of cervical cancer, which
may look like an ulceration or mass. 
If a tumor develops inside the endocervical canal, there may be an enlarged,
indurated cervixwith a smooth surface, referred to as a "barrel shaped cervix". 
Any visible lesion should be biopsied, and any cervix that is unusually firm or
expanded should be sampled with biopsies and endocervical curettage, even if there
is no evidence of neoplasia on a pap smear. 
Heavy bleeding is a major risk when biopsying visible cervical lesions, so hemostatic
agents like Monsel solution should be used if needed. 
The biopsy can come back either as carcinoma in situ or invasive cervical cancer. 
Carcinoma in situ is considered stage 0 cervical cancer, and can be treated with an
excisional procedure cold knife conization or loop
electrosurgical excision procedure. 
For invasive cervical cancer, a CT or MRI can be done for further staging. 
Stage I cervical cancer is strictly confined to the cervix and the uterine corpus, and
can be further broken down in IA and IB. 
IA is when the cancer can only be seen under the microscope and has invaded less
than 5 millimeters into the cervical stroma, and IB can sometimes be seen with the
naked eye and is when cancer has invaded more than 5 millimeters into the cervical
stroma. 
Stage II cervical cancer has spread beyond the uterus, but hasn’t reached the lower
third of the vagina or the pelvic wall, and can also be IIA or IIB.
IIA cervical cancer is limited to the upper two thirds of the vagina, but the
parametrium, which is a layer of connective tissue that separates
the uterus and cervix from the urinary bladder, isn’t affected. 
IIB cervical cancer has invaded the parametrium, but hasn’t spread to the pelvic
wall. 
Stage III cervical cancer has 3 substages depending on involvement. 
Stage IIIA has spread to the lower third of the vagina, but hasn’t reached the pelvic
wall. 
Stage IIIB has spread to the pelvic wall or has invaded the ureters,
causing hydronephrosis - or urine buildup in the kidneys. 
And stage IIIC has spread to the pelvic or paraaortic lymph nodes. 
Finally, with stage IV cervical cancer, the cancer has either spread to adjacent pelvic
organs, like the bladder or rectum, in which case it’s IVA, or has spread to distant
organs, in which case it’s IVB. 
Now, usually, stage I cervical cancer is discovered following a pap smear. 
And good news is, for females with stage IA cervical cancer who wish
to bear children in the future, cold knife conization can be done to remove the
cancer, and the uterus is left in place, or a trachelectomy, which is when just
the cervix and the upper third of the vagina is removed, can be done. 
With cold knife conization, a histopathological examination should be performed to
see if the edges of the removed piece have any cancer cells. If they do, the
conization can be repeated, or a radical trachelectomy can be done, with the latter
being preferred if the cancer has invaded into blood or lymph vessels. 
Alternatively, if the female with stage IA cervical cancer doesn’t want to
preserve fertility, a total hysterectomy can be done, which is when both
the uterus and the cervix are removed. 
During the hysterectomy, pelvic and paraaortic lymph nodes are sometimes also
removed to double check if the cancer has spread. 
For stages IB and IIA, the main treatment options are hysterectomy, radiotherapy,
and chemotherapy.
Radiotherapy is usually given as brachytherapy, which is when a dose of radiation is
given locally, to the cervix and vagina. 
Chemotherapy is done with cisplatin, and fluorouracil can also be added. 
And sometimes radiation and chemotherapy are given at the same time, in which
case the term “chemoradiation” is used. 
For stages IIB through IVA, chemoradiation is the standard treatment, and
a hysterectomy is not routinely performed. 
For stage IVB cervical cancer, palliative treatment with chemoradiation can be done
to help relieve symptoms. 
To end on a bright note, remember that anti-HPV vaccination is available. 
In the United States, there’s a vaccine called Gardasil 9, which targets 9 HPV strains
- the 7 high risk strains, 16, 18, 31, 33, 45, 52 and 58, as well as 2 other strains, 6
and 11, which are considered low risk for cervical cancer, but can cause genital
warts. 
HPV vaccination is recommended in both females and males, ideally between the
ages of 11 and 12 years old, with a second dose given 6 to 12 months later. 
Alternatively, a three dose regimen can be used, where the second and third doses
are given 2, and respectively 6 months later. 
Males should be vaccinated because they may be asymptomatic carriers of a high
risk HPV strain that could cause cervical cancer in a female partner. 
Alternatively, catch-up vaccination can be done in individuals 13 to 26 years old, who
weren’t vaccinated before. 

Summary
Alright, as a quick recap… Cervical cancer is almost always caused by an HPV
infection, most frequently with HPV strains 16 and 18. 
Screening for cervical cancer can be done with a pap test every three years in
females between the ages of 21 and 65. 
Abnormal pap test results include the presence of atypical squamous cells, which
can be either ASC-US or ASC-H, or the presence of cervical squamous
intraepithelial lesions, which can be either LSIL or HSIL. 
A reflex HPV test can be done at the same time as the pap smear, which can come
back positive or negative for HPV. 
Further management depends on the age of the individual. 
In females older than 25, a colposcopy should be done when the pap test results are
HSIL or ASC-H, or for an ASC-US or LSIL result and a positive reflex HPV test.
Depending on the result of the colposcopy, treatment options include observation, for
all types of cervical intraepithelial lesions, or a diagnostic excisional procedure, like
loop electrosurgical excision procedure, or cold knife conization, for CIN 2 and 3
lesions.
In females between the ages of 21 and 24, more conservative options, like
observation with pap smears at 12 and 24 months, are preferred for ASC-US and
LSIL lesions, and a colposcopy is done for HSIL and ASC-H lesions. 
So with appropriate screening, cervical intraepithelial neoplasia can be removed
before it even becomes cancer! 
If it does go by undetected, cervical cancer per se can present with vague symptoms
like postcoital bleeding or irregular vaginal bleeding, and a colposcopy and
sample biopsiesshould be done even if a lesion is not visible to the naked eye. 
Depending on stage, cervical cancer can be treated with cold knife conization, a
radical trachelectomy, a total hysterectomy, and chemoradiation can be done.
Thankfully, it can be preventing by vaccinating against high-risk HPV strains, either
between the ages of 11 and 12, or catch-up vaccination between the ages of 13 to
26.

Vulvar cancer
Over 90% of vulvar cancers are squamous cell carcinomas, which develop from
the squamous epithelium of the vulva. 
The other 10% of vulvar cancers are melanomas, which develop from melanocytes,
and vulvar adenocarcinomas, which develop from glandular cells, like those that
make up Bartholin's glands on either side of the vaginal opening. 
A particular type of adenocarcinoma is Paget’s disease of the vulva - which is a type
of cancer that usually develops in the ducts of the breast, but can rarely develop in
other locations, such as the vulva. 
Ok, now, more than 50% of vulvar squamous cell carcinomas are in relation to an
HPV infection, particularly high risk strains, like HPV 16 and 18 - just like
with cervical cancer. 
And just like cervical cancer, vulvar cancer starts out as vulvar intraepithelial
neoplasia, and it may take many years for it to even progress to cancer. 
Other risk factors for squamous cell carcinomas include
smoking, immunosuppressiveconditions like an HIV infection, and lichen sclerosus,
which is a skin disorder than frequently affects the genitals, making the skin become
very thin and white, like cigarettepaper. 
For the melanoma type of vulvar cancers, risk factors include a family history
of melanoma, or a personal history of melanoma or dysplastic nevi, which are
atypical moles, in other locations on the body. 
Additionally, individuals with cervical or vaginal cancer have a higher risk of vulvar
cancer, probably because they can all be caused by high risk HPV strains. 
Symptoms vary depending on histologic subtype, but at the end of the day, there’s
always a vulvar lesion, and pruritus - the fancy word for itching. 
Sometimes there may also be associated pain, bleeding or discharge. Squamous
cell carcinomas usually look like a red, pink or white bump, or it may look like a wart,
or an open sore that doesn’t heal. 
Vulvar melanomas, on the other hand, are usually black or dark brown - and
sometimes they may start in a mole, in which case the ABCDE rule can be used to
distinguish the cancer from the mole. A is for asymmetry, which means one half of
the mole looks different than the other, B is for border irregularity, C is for color,
meaning there are various colors within the same lesion, D is for a diameter wider
than 6 millimeters, and E is for evolving - meaning the mole changes in size, shape
or color over time. 
Adenocarcinomas that develop from Bartholin’s glands, present like a distinct lump
on either side of the opening of the vagina. Finally, Paget’s disease of
the vulva presents as a red, scaly, sore lesion. 
To diagnose vulvar cancer, a biopsy is done. If subclinical vulvar lesions are
suspected, a vulvoscopy may also be done - which is when a colposcope is used to
get a zoomed-in view of the vulva, and any suspicious looking areas are biopsied. 
The biopsy can be an excisional biopsy, when the lesion is small and it’s removed
entirely, along with a little bit of tissue around it, or a punch biopsy, when just a
sample is taken. 
The biopsy confirms the malignant character of the lesion, and it
also differentiatesbetween the histologic subtypes, and this guides further treatment. 
Additionally, for squamous cell carcinoma, a biopsy may identify precancerous
lesions - which may be either low grade squamous intraepithelial lesion, or LSIL, or
high grade squamous intraepithelial lesion, or HSIL, depending on how atypical the
cells look.
LSIL vulvar intraepithelial neoplasia is equivalent to warts, and they can be treated
with local cytodestructive therapies like podophyllotoxin, which are applied by the
individual, or acid and acid, which are applied by a clinician. 
Immunotherapeutic agents like imiquimod creams can also be given, and they’re
also applied by the individual. Alternatively, the lesion can be removed
through ablativeprocedures, like cryoablation, laser ablation, or electrocautery, or
excisional procedures.
Management options for HSIL lesions include topical treatment, ablative procedures,
a wide local excision, which is when the mass along with 2 centimeters of apparently
healthy tissue surrounding it are removed, or a skinning vulvectomy, which involves
removing only the top layer of skin affected by cancer - but this is not commonly
done in practice. 
If the biopsy comes back as invasive vulvar cancer, no matter the
histologic subtype, staging is done based on the TNM system - where T stands for
primary tumor size and local extension, N for lymph node metastases and M for
distant metastases. 
Sometimes a chest X-ray, a CT scan, or an MRI may be done to look for lymph node
and distant metastases.
So, stage I vulvar cancer is when the cancer is smaller than 2 centimeters, confined
to the vulva or perineum, and there are no lymph node or distant metastases. 
Stage II is when the cancer is growing into the lower third of the urethra,
the vagina or the anus, but there are still no lymph node or distant metastases. 
Stage III is the same as stage II, except there are lymph node metastases, but no
distant ones. And finally, vulvar cancer is stage IV when there are distant
metastases, no matter the tumor size, local extension, or lymph node metastases. 
The mainstay of treatment is surgical excision of the cancer lesions. 
The choice of procedure may range from a wide local excision to a partial or
complete radical vulvectomy, which is when part of, or, respectively the
entire vulva is removed, along with the inguinal lymph nodes. 
Radiation therapy, chemotherapy or immunotherapy may also be used after
surgery. 

Summary
Alright, as a quick recap: over 90% of vulvar cancers are squamous cell carcinomas,
and more than 50% of these are in relation to an HPV infection. 
The other 10% of vulvar cancers are either melanomas or adenocarcinomas, and a
particular type of adenocarcinoma is vulvar paget’s disease. 
Vulvar cancer presents as an itchy skin lesion, which may vary in color, shape and
size, and diagnosis is done with a biopsy that can distinguish between the various
histologic subtypes. 
Treatment for LSIL lesions can be done with local cytodestructive therapies like
podophyllotoxin, or acid and acid, or immunotherapeutic agents
like imiquimod creams. 
Alternatively, the lesion can be removed through ablative procedures, like
cryoablation, laser ablation, or electrocautery, or excisional procedures. 
HSIL lesions can be treated with topical treatment, ablative procedures or surgical
procedures like a wide local excision or a skinning vulvectomy. 
Invasive vulvar cancer is treated surgically, and a wide local excision, or a partial or
complete vulvectomy with inguinal node removal may be done. 
Radiation therapy, chemotherapy or immunotherapy may also be used after surgery.

Prostate disorder and cancer

On the Urology ward, two people came in. 
The first is 63-year-old Joseph who complains of difficulty with urination. 
More specifically, he says he has trouble initiating his stream of urine, and
after urination, his bladder still feels full. 
He also wakes up several times each night feeling the need to urinate. 
These symptoms have been present for the past few years, but have gradually
become worse. 
Digital rectal examination revealed symmetrically enlarged, smooth, firm,
nontender prostate with rubbery or elastic texture. 
The second is Sam, a 72-year-old African-American individual who comes in
with lower back pain that is not relieved by rest or position changes and has been
increasing over the past couple of months. 
He has also noticed recent feelings of fatigue and weight loss, which he attributes to
decreased appetite. 
On further history, he consumes a diet low in fiber and high in saturated fat and
red meat. 
On digital rectal examination, an irregular, hard lump is palpated in the posterior of
his prostate. 
Labs show increased alkaline phosphatase and total PSA levels with decreased free
to total PSA ratio.
Both Joseph and Sam have different forms of prostate disorders! 
Let's first remind ourselves about physiology real quick. 
The prostate is a small gland whose job is to secrete an alkaline milky liquid that
joins the sperm and the semen . To do that, it sits under the bladder and in front of
the rectum. 
That’s important because when we do digital rectal exam, we’re able to palpate the
posterior of the prostate. 
The urethra goes through the prostate before reaching the penis. 
And that part of the urethra is called the prostatic urethra. 
Now, the prostate can be divided into a few zones and this is high yield! 
The peripheral zone, which is the outermost posterior section, is the largest of the
zones and contains about 70% of the prostate’s glandular tissue. 
Moving inward, the central zone contains about 25% of the glandular tissue. 
Last, is the transitional zone, which contains around 5% of the glandular tissue, and
is located in the periurethral region of the prostate. 
The transitional zone gets its name because it contains transitional cells which are
also found in the bladder. 
At the microscopic level, the prostate is made up of stroma, or connective tissue, and
glands. 
Each of these glands is surrounded by a basement membrane and lined by an outer
layer of cuboidal basal cells and an inner ring of luminal columnar cells, which are
within the lumen or center of the gland. 
An important thing to remember is that both the basal cells and luminal cells of
the prostaterely on stimulation from androgens for survival,
including testosterone which, at the prostate, is converted by the enzyme 5α-
reductase into the more potent dihydrotestosterone. 
Okay, now, the first prostate disorder is prostatitis or inflammation of the prostate. 
This can be either acute or chronic. 
Acute prostatitis is usually due to bacteria. In young adults, that’s most
commonly Chlamydia trachomatis and Neisseria gonorrhoea, whereas in older
individuals, it’s usually Escherichia coli, followed by Pseudomonas. 
Now, acute prostatitis classically presents as dysuria with fever and chills. 
A particularly high-yield fact for your test is that on a digital rectal exam,
the prostate will be warm, tender and boggy. 
Also, lab analysis of prostatic secretions will show increased white blood cells and
culture will reveal the pathogenic bacteria. 
Chronic prostatitis, on the other hand, can be bacterial or nonbacterial, such as
secondary to previous infection, nerve problems or chemical irritation. 
Similarly to acute prostatitis, it also presents as dysuria, but the key hint here is that
the individual is typically afebrile and also complains on pelvic or lower back pain. 
On digital rectal examination, the prostate may feel normal, tender, or
boggy. Prostatic secretions will again show increased white blood cells, but culture
may be negative in nonbacterial cases.
Moving on to benign prostatic hyperplasia or BPH for short. 
This is hyperplasia of both the stroma and the glands of the prostate. 
For your tests, note that it’s hyperplasia, which is an increase in the number of cells,
and not hypertrophy, which would mean an increase in the size of the cells. 
It is driven by 5α-reductase activity in the prostate which increases with age, leading
to increased dihydrotestosterone production. 
Dihydrotestosterone then makes prostate cells live longer and multiply faster. A high
yield fact to remember is that this is actually a normal process of aging, and around
50% of men develop BPH by the age of 60. 
Another important thing to remember is that BPH is not associated with any
increased risk for developing prostate cancer. 
Rather, as the prostate gland enlarges, small hyperplastic nodules can form within
it. 
A particularly high-yield fact is that these hyperplastic nodules will typically form in
the periurethral region of the prostate. 
When these nodules or the prostate tissue itself compress the prostatic urethra, it
becomes more difficult for urine to pass though, leading to a weak and inconsistent
stream of urine, called dribbling. 
Since the prostate sits just below the bladder, when it’s enlarged, it can
cause bladderoutflow obstruction. 
Also the person might have to strain when urinating to overcome the obstruction,
have pain during urination called dysuria, or trouble initiating and
stopping urination called hesitancy. 
So the urine builds up in the bladder causing it to dilate, creating a constant sense of
incomplete bladder emptying and overflow incontinence. 
In response, the smooth muscle walls of the bladder will contract harder, and this
leads to bladder hypertrophy were the walls thicken and become irritable. 
This increases the frequency of urination at night, which is called nocturia. 
Now, one complication of the stagnation of urine in the bladder is that it promotes
bacterial growth, and can lead to urinary tract infections. 
Also, the urine can build up back into the ureter and the kidney,
causing hydronephrosis, or dilation of the renal pelvis and calyces. 
Severe long-standing hydronephrosis can subsequently compress the renal
parenchyma, resulting in atrophy of the renal medulla and cortex.
Diagnosis of BPH starts with digital rectal examination. 
What’s high-yield here is that the prostate will be symmetrically enlarged, smooth,
firm, nontender with rubbery or elastic texture. 
Levels of prostate specific antigen or PSA, a substance produced by
healthy prostate cells, will be also elevated, since there are more cells around
making the PSA. 
However, that’s not specific for BPH and can be true for a handful of
other prostatedisorders.
Treatment of BPH focuses on relieving the obstruction and allowing the urine to flow
normally. 
This can be done through medications like finasteride, a 5α-reductase inhibitor. 
For your test, remember that 5α-reductase inhibitors shrink the prostate gland by
inhibiting the conversion of testosterone into dihydrotestosterone. 
Another high-yield fact to keep in mind is that it can take up to 6-12 months for
symptom improvement and side effects include decreased libido and erectile
dysfunction. 
Next, α1-antagonists like terazosin and tamsulosin can bind to α1 receptors on
the smooth muscles in the neck of the bladder, the prostate, and urethra, causing
them to relax and allowing urine to pass. 
These are usually preferred for symptom improvement within days to weeks. Side
effects include orthostatic hypotension and dizziness. 
Another type of smooth-muscle relaxants is antimuscarinics,
like tolterodine or oxybutynin. 
These are especially useful for those with irritable bladder symptoms. 
For your test, remember that they are avoided in individuals with increased post-
void residual volume, which is the volume of urine retained in the bladder after a
voluntary void. 
This is because relaxing the bladder can increase the urinary retention even more. 
Next, phosphodiesterase type 5, or PDE5 inhibitors like tadalafil can be also used,
especially in individuals with concurrent erectile dysfunction. 
In some cases, surgical procedures like ablation or transurethral resection of
the prostate, or TURP, can be done to remove part or all of the prostate.
Alright, now, the next prostate disorder is prostatic adenocarcinoma. 
A high yield epidemiology fact to remember is that this is the most common cancer
and the second most common cause of cancer death in males. 
Risk factors include age older than 50 and if the person is of African descent. 
An extremely high-yield fact you should absolutely remember is
that prostateadenocarcinoma most commonly occurs in the posterior peripheral zone
of the prostate. 
The reason why that’s so important is that it is actually far away from the urethra. 
As a result, these tumors can grow quite large before they cause problems
with urination. 
Over time, if the cancer does compress or invade the urethra or bladder, it can
cause difficulty urinating, bleeding, and pain with urination and ejaculation.
If the cancer becomes metastatic, it most commonly spreads via
the vertebral venous plexus, also called Batson plexus, to the bones of the axial
skeleton, like the vertebrae or pelvis, resulting in hip or lower back pain. 
The key symptom here to differentiate it from benign causes of back pain is that it
gets worse at night and not relieved by rest or position change. 
A high-yield fact to know is that these metastatic lesions are osteoblastic or sclerotic,
rather than lytic ones.
For diagnosis, on digital rectal examination, the tumor can be easily palpated in the
posterior of the prostate and feel like an irregularly hard lump. 
Prostate cancer can also cause elevation in certain tumor markers like prostatic acid
phosphatase, or PAP for short, and PSA. 
Since PSA elevation is non-specific, what helps determine the risk of cancer is
calculating the free to total PSA ratio. 
Specifically, PSA circulates in the serum in two ways: either on its own, called free
PSA, or bound to other proteins. 
For unclear reasons, the lower the free to total PSA ratio, the higher the risk of
cancer and the greater the necessity of a prostate biopsy. 
Now, in a biopsy of prostate adenocarcinoma, what we would classically see are
small glands that infiltrate the normal prostatic tissue. 
A characteristic finding is that the nuclei of the tumor cells have dark nucleoli. 
Based on the architecture of the tumor cells, the tumor can then be scored using the
Gleason grading system. 
The Gleason scale identifies the two most common architecture patterns within
the prostate tissue and assigns a score between one and five to both of them. 
A score of 1 represents normal, well differentiated cells, and a score of 5 represents
highly abnormal cells that barely resemble the normal prostate tissue. 
Once the primary and secondary patterns have each received a score from one to
five, these two numbers are added together, resulting in a total Gleason score
between two and 10 with two representing low-grade tumors and 10
representing high-grade, dangerous tumors. 
Now, regarding metastatic disease, radionuclide bone scanning can be also done to
look for bone lesions. 
A high yield fact to remember is that If these are present, serum alkaline
phosphatase will be elevated as well, and this can be a useful screening tool for
recurrent bone metastasis. 
In terms of treatment, when the tumor is confined to the prostate, and hasn’t
metastasized, surgical excision of the prostate, also known as prostatectomy, is
done along with radiotherapy and hormonal therapy. 
Now, the most commonly tested medications used in hormonal therapy
are leuprolide and flutamide. Leuprolide is a gonadotropin-releasing
hormone or GnRH analog that when administered in continuous fashion, results in
downregulation of GnRH receptors in the pituitary, which then reduces LH and FSH
secretion, both of which promote androgensecretion and the growth of prostate
cancer cells. 
Flutamide is an androgen receptor antagonist. 
So both leuprolide and flutamide deprive cancer cells of androgen stimulation. 
Sometimes older individuals with low stage non-metastatic prostate cancer might
decide to undergo active surveillance instead since prostatectomy can cause certain
complications, like damaging the prostatic plexus, resulting in erectile dysfunction. 
If the tumor has metastasized however, treatment options include radiation therapy,
chemotherapy, and hormonal therapy. 

Summary
All right, as a quick recap, prostatitis can be acute, which is usually caused by
bacteria, and causes fever and dysuria, or chronic, which can be bacterial or non-
bacterial, and causes dysuria and back pain. 
Benign prostatic hyperplasia is a normal phenomenon in individuals older than 50
and does not increase the risk for cancer. 
It manifests as a smooth, elastic, firm nodular enlargement in the periurethral zone of
the prostate. 
Classic presentation include dribbling, dysuria, hesitancy, increased frequency
of urinationand nocturia. 
Complications include UTI’s and hydronephrosis. 
Prostatic adenocarcinoma typically develops as an irregular hard lump in the
posterior peripheral zone of the prostate.
It can be asymptomatic or present with back pain later on due to bone metastases. 
Tumor markers include PAP and PSA. 
If bone metastasis occurs, serum alkaline phosphatase will be elevated. 
Finally, the diagnosis needs to be confirmed with a biopsy.
Now, let’s not forget about our cases! 63-year-old Joseph has the classic symptoms
of benign prostate hyperplasia: straining on urination, hesitancy and nocturia. 
The key finding to point us towards BPH is a symmetrically enlarged, smooth, firm
and nontender prostate on digital rectal examination. 
This is disorder is particularly common for his age. 
He got started on finasteride and now he is doing much better! 
Regarding 72-year-old Sam, he came in with low back pain not relieved with rest or
posture changes, as well as fatigue, anorexia and weight loss. 
On digital rectal examination, an irregular hard lump was palpated in the
posterior prostate. 
This along with the increased alkaline phosphatase and PSA levels and decreased
free to total PSA ratio is characteristic for bone metastasis
from prostatic adenocarcinoma. 
Other clues include his age, African-American descent, and low fiber diet, which are
all risk factors for the development of prostate adenocarcinoma. 
The diagnosis was confirmed with a prostate biopsy and a radionuclide bone
scan showing spine metastasis. 
He started receiving hormonal therapy, specifically leuprolide.

Renal cyst and cancer

Renal masses can develop in both adults and children, and sometimes, they're due
to genetic mutations. 
These masses may be either cysts or tumors, and they can be discovered
incidentally during an abdominal ultrasound or a CT-scan or when an individual has
symptoms like abdominal or flank pain. 
Renal cysts can be simple or complex, and they can also be solitary - meaning
there’s just one cyst, or there can be multiple cysts - sometimes affecting both
kidneys.
Simple cysts are the most common type of renal mass, and they typically occur in
adults with otherwise healthy kidneys. 
On an abdominal ultrasound, they’re usually smaller than 1 centimeter, but can be
up to 4 centimeters. They’re round and have a thin regular wall and are filled with
liquid which makes them anechoic - so it basically looks like a small balloon filled
with black fluid. 
Additionally, there can also be some fine septa and calcifications within the simple
cyst. 
Usually they’re asymptomatic, and don’t need treatment. 
On the other hand, complex cysts are larger than 1 centimeter. On an ultrasound,
they have thick, irregular walls and are multilocular- meaning they
have septations within, that separate the cyst cavity into compartiments.
Complex cysts can cause symptoms like flank pain, and they can cause
complications like infections, hemorrhage, and hypertension.
An infected cyst can cause symptoms like fever and fatigue. 
Sometimes, the infection can spread to the renal parenchyma, causing an acute
pyelonephritis with symptoms like fever, acute flank pain or diffuse abdominal
tenderness.
A CBC shows leukocytosis and neutrophilia, and the ESR and CRP are elevated. 
If the infection is limited to the cyst, then the urinalysis may be normal, whereas if the
cyst causes acute pyelonephritis then pyuria, bacteriuria and proteinuria are
present. 
Blood cultures may be positive with both a simple cyst infection and acute
pyelonephritis, whereas urine cultures are typically positive only with acute
pyelonephritis. 
An ultrasound can show a thick cystic wall. 
The ultrasound can show a clear separation between urine, which is a low density
fluid, and pus, which is a high-density fluid. 
The initial treatment of an infected cyst is empirical. If the symptoms are mild, then
an oral fluoroquinolone like ciprofloxacin or trimethoprim-sulfamethoxazole is given
for 4 to 6 weeks. 
If the symptoms are severe, then IV ciprofloxacin is given until the symptoms resolve
and then oral ciprofloxacin is given to finish the treatment course. 
If the blood or urine cultures identify a pathogen, then the antibiotic is adjusted
accordingly. 
Now, if the individual doesn’t respond to antibiotic therapy within 72 hours or has
persistent fevers for more than a week, then a CT-scan is done. 
If the cyst is larger than 3 centimeters, then percutaneous drainage may be needed. 
Another complication is cystic hemorrhage which can cause hematuria. 
Cystic hemorrhage is treated with bed rest, pain medication like acetaminophen, and
aggressive fluid hydration - usually more than 2 liters per day to prevent blood clot
formation.
If there’s severe bleeding that causes hemodynamic instability, a blood
transfusion may be required, and with persistent
bleeding, segmental arterial embolization, or surgery may be needed. 
Finally, hypertension occurs when one or more cysts compress the renal
parenchyma. In part, that’s because the epithelial cells that form the wall of the cysts
release renin, which stimulates angiotensin and aldosterone,
causing vasoconstriction of the renal artery and sodium retention, leading
to hypertension. 
Treatment relies on ACE inhibitors - like captopril, or angiotensin receptor blockers -
like candesartan, with a goal of keeping the blood pressure below 125/75 mmHg.
Now, every complex cyst, regardless of whether there are complications, should be
further worked up to see if there’s an underlying malignancy. That starts with
a urinalysis, which might show hematuria. 
Also an abdominal CT-scan with contrast should be done to classify the cyst
according to the Bosniak system - which has 5 grades - I, II, IIF, III, and IV. 
The higher the grade, the more malignant it appears on the CT scan.
Sometimes, the diagnosis is still uncertain after CT and MRI scans, and in those
situations a percutaneous needle biopsy may be done to determine whether the cyst
is benign or malignant.
Now, in terms of the grades - grade I and II are simple cysts. 
With grade I, there’s a single cyst or multiple cysts without septa or calcifications. 
With grade II, there are only fine septa and calcifications may be seen within the
cyst. 
Grade I and grade II cysts have no malignancy risk, so no further evaluation is
needed. 
Next, there’s a grade IIF cyst - which is between grade II and grade III; there are
multiple fine septa within the cysts, the wall is thickened, and there are calcifications
in the wall or septa. There’s a low risk of malignancy, so an abdominal CT-scan or
an MRI is done within 6 months to see if the cyst has gotten bigger - in which case
surgical resection may be needed. 
With grade III and grade IV cysts, there are many septations within and the wall is
thick and irregular. 
About half of grade III cysts, and nearly all grade IV cysts are malignant, so surgical
resection of the cyst or radiofrequency ablation are frequently needed. 
Radiofrequency ablation involves using a radiofrequency generator, to generate
high-frequency current to heat a needle. That hot needle is inserted into the tumor,
which destroys the tissue. 
Now, let’s switch gears and talk about renal cell carcinoma or RCC for short.
RCC originates in the renal cortex, and it’s the most common type of renal cancer in
the elderly. 
A malignant complex cyst is typically RCC, but not all RCCs arise from a complex
cyst. 
Some individuals are asymptomatic and diagnosed incidentally when a renal mass is
found on an abdominal CT-scan. Others have symptoms, and the classic triad
is flank pain, hematuria, and palpable abdominal mass. 
Lab studies include a CBC- which may show anemia or in rare cases, erythrocytosis-
when the tumor secretes erythropoietin. 
Liver function tests may show elevated alkaline phosphatase if there’s hepatic
dysfunctionor bone metastasis. 
If there’s a high alkaline phosphatase, bone scintigraphy is done to check for bone
metastasis. 
Finally, if there’s a paraneoplastic syndrome, the serum calcium may be elevated
because RCC can increase the release of calcium from bone. 
An ultrasound typically shows a complex cyst, an abdominal CT-scan can show local
and regional involvement, and a chest CT-scan can show pulmonary
or mediastinal lymph node metastasis.
RCC is staged according to the Tumor-Node-Metastasis system or TNM system into
four stages, where the more aggressive and widespread the disease, the higher the
stage. 
Now, a partial nephrectomy is done when there’s an isolated solid renal mass with
no evidence of distant metastases, as long as the tumor is under 4 centimeters or
the individual has only one kidney. 
A total nephrectomy is done when the tumor is located in the center of the kidney,
when there’s involvement of a nearby lymph node, renal vein or inferior vena cava,
or when the tumor has spread to the adrenal gland. 
If the individual is not a surgical candidate, then radiofrequency ablation can be
done. 
In individuals with metastatic disease, histological biopsies of the metastatic site are
typically done, and the majority are clear cell carcinomas. 
If there’s a single metastasis, it’s usually surgically removed, and then a
debulking nephrectomy is typically done. 
After that, treatment is chosen based on a variety of risk factors including a high
serum calcium, high neutrophil count, high platelet count,
low hemoglobin concentration, functional impairment, and rapid disease
progression. 
Individuals with at least one risk factor, are treated with a combination
of monoclonalantibodies like nivolumab plus ipilimumab. 
Individuals with no risk factors are usually monitored closely and if the tumor grows,
then they’re treated with a vascular endothelial growth factor tyrosine kinase
inhibitor like sunitinib or pazopanib. 
Finally, there’s autosomal dominant polycystic kidney disease or ADPKD which is
caused by mutations in either the PKD1 or PKD 2 gene. 
Individuals can have flank pain and abdominal pain, and hematuria if a cyst bleeds
into a collecting tubule. There can also be increased thirst, polyuria, nocturia- which
happens because with ADPKD, individuals are unable to concentrate their urine.
They can also develop nephrolithiasis which can cause acute acute flank pain. 
An abdominal ultrasound shows multiple cysts in one or both kidneys, and the
diagnosis depends on the person’s age and family history. 
In individuals with an unknown family history aged between 15 and 39 years, there
must be at least 3 kidney cysts across both kidneys.
In individuals between 40 and 59 years old, there must be at least 2 cysts in each
kidney and in individuals older than 60, there must be at least 4 cysts in each
kidney. 
In individuals with a family history of ADPKD caused by PKD1 mutation that are
aged between 15-30 years, there must be at least 2 cysts across both kidneys. 
In individuals aged between 30-59 years old, there must be 2 cysts in each kidney,
and in individuals older than 60, there must be four cysts in each kidney. 
In individuals with a family history of ADPKD caused by PKD2 mutation, genetic
testing is done to identify the mutation and confirm the diagnosis. 
If the ultrasound is uncertain, then an abdominal CT-scan, an MRI, or genetic
testing can be done. 
Just like complex cysts, ADPKD cysts can cause complications like recurrent urinary
tract infections, hemorrhage, and hypertension. 
Now, individuals with ADPKD also have extrarenal manifestations. A life-threatening
one is a berry aneurysm off of the circle of Willis in the brain. These aneurysms can
rupture and cause subarachnoid or intracerebral hemorrhage, which can cause a
sudden headache, a stiff neck, photophobia, and double vision. 
Some other extrarenal manifestations are hepatic and pancreatic cysts that can be
seen on an abdominal ultrasound, colonic diverticula which can cause abdominal
pain, diarrhea, and positive hemoccult test- and can be diagnosed
during colonoscopy, and abdominal wallhernias- which can be seen on physical
exam. There can also be mitral valve prolapse and aortic regurgitation which can be
seen on echocardiography. 
With ADPKD, the renal function is generally normal, but then starts to decline
as chronic renal disease begins to develop in the fourth decade. 
Dietary sodium should be restricted to less than 2 grams per day. 
Hypertension is treated with an ACE-inhibitor or an ARB. In individuals between 18
and 55 years old with an eGFR above 25 milliliters per minute per 1.73 meters
square, a vasopressin receptor antagonist like tolvaptan can be used to slow the
progression of the renal disease. 
In individuals between 18 and 55 years old with an eGFR below 25 millimeters per
minute per 1.73 meters square, peritoneal dialysis or hemodialysis may be
necessary. 
Occasionally, a nephrectomy is done in individuals with recurrent
or refractory urinary tract infections, with chronic hematuria that requires blood
transfusions, or with chronic pain. 
Finally, if an individual develops end-stage renal disease- meaning an eGFR below
15 milliliters per minute per 1.73 meters squared, then hemodialysis or renal
transplantationcan be done. 

Summary
Alright, as a quick recap, simple cysts are typically asymptomatic and
the ultrasound shows a round small mass with thin walls and anechoic fluid within.
No treatment is necessary. 
Complex cysts can be asymptomatic or present with flank pain, and
the ultrasound shows a larger mass with irregular walls and septations. 
Complex cysts can present with complications like- infection- in which case
there’s neutrophilia and ESR and CRP are elevated. 
Urinalysis can show pyuria, bacteriuria and proteinuria. 
Urine and blood cultures are also done, and it’s initially treated with oral or
IV ciprofloxacin. 
Other complications include -hemorrhage- in which case bed rest, analgesics and
adequate fluid intake is recommended. 
Finally, for hypertension, ACE inhibitors or ARBs are administered. 
If the ultrasound is uncertain, or with all complex cysts, an abdominal CT-scan is
done, and cysts are classified according to Bosniak’s system. 
Type I and II cysts are benign and don’t require any treatment, while type IIF, III, IV
can be malignant and require surgical resection or radiofrequency ablation. 
Renal Cell Carcinoma can cause a triad of flank pain, hematuria, and abdominal
mass. 
An ultrasound and a CT scan can be done to classify the tumor in the TNM system. 
In individuals with no metastasis, surgical resection is usually done. 
In individuals with metastatic disease, biopsies of the metastatic sites are done to
confirm the diagnosis.
Prior to systemic therapy, a debulking nephrectomy is done. 
After that, treatment with nivolumab plus ipilimumab is done if there are risk factors
and treatment with sunitinib or pazopanib is done if there aren’t any risk factors. 
Autosomal dominant polycystic kidney disease can be diagnosed based on
an ultrasoundor with genetic testing. 
Extrarenal manifestations of ADPKD include cerebral aneurysms, hepatic
and pancreatic cysts, colonic diverticula, mitral valve prolapse, and aortic
regurgitation.
Treatment relies on dietary sodium restriction, treating hypertension with ACE-
inhibitors or ARBs, giving tolvaptan when eGFR is above 25 millimeters per minute
per 1.73 meters square, and with end stage renal disease dialysis and renal
transplantation can be done.

Thyroid nodules and cancer

On the endocrinology ward, two individuals came in. 
Both individuals complained about feeling a lump on their necks, but reports no other
symptoms. 
The first one is 49 year old Dasha who as a child, lived close to Chernobyl. 
The other one is 27 year old Mike, who's family history involves multiple endocrine
neoplasia type 2A. 
On exam, they each had a painless mass on their thyroid. 
Both people had normal T3, T4, and TSH levels. 
They underwent thyroid echography, which showed cold nodules. 
Afterwards, fine-needle biopsies were done. 
Both individuals had tumors on their thyroids. 
First, let’s refresh some info on the thyroid. 
The thyroid gland is an endocrine gland located in the neck. 
The thyroid gland is made up of thousands of follicles, which are small spheres lined
with follicular cells. 
Follicular cells convert thyroglobulin, a protein found in follicles, into two iodine-
containing hormones, tri-iodo-thyronine or T3, and thyroxine or T4. 
Once released from the thyroid gland, these hormones enter the blood and bind to
circulating plasma proteins. 
Once inside the cell T4 is mostly converted into T3, at which point it can exert its
effect. 
T3, among other effects, speeds up the basal metabolic rate, increases cardiac
output, stimulates bone resorption and activates the sympathetic nervous system. 
The thyroid is also made up of parafollicular or C cells, which are near the follicles. 
These cells produce calcitonin, a hormone that lowers blood calcium levels by
inhibiting osteoclasts. 
Calcitonin also inhibits renal tubular cell reabsorption of calcium, allowing
the calcium to be excreted in the urine. 
Now, DNA mutations can cause thyroid cells to become cancerous. 
For example, a mutation might change a proto-oncogenes like RET and BRAF,
which are genes that code for proteins that promote cell growth and proliferation,
into oncogenes. 
That would mean that the proteins force the cell to be stuck in the "on" position,
always dividing, and that causes the thyroid cell to turn into a tumor. 
There are other genes, called tumor suppressors, like TP53, that normally slow down
cell division or make cells die if they divide uncontrollably. 
DNA mutations might also turn off tumor suppressor genes, which
allows thyroid cells that try to divide uncontrollably to go unchecked. 
Let’s start by talking about thyroid adenomas which are benign and solitary growths
of the thyroid. 
A high yield fact is that typically, these nodules are non-functional, so they don't
produce thyroid hormones, and these are called "cold" nodules. 
In rare cases, the nodules can produce hormones regardless of TSH secretion, in
which case they’re called hot, or toxic, nodules and they can lead
to hyperthyroidism. 
On histology, thyroid adenomas are follicular and there’s no capsular or vascular
invasion. 
Moving on to thyroid carcinomas and there are 3 types: differentiated, medullary,
and anaplastic. 
Let’s start talking about differentiated thyroid cancer, the cancer arises from follicular
cells, and it's known as differentiated because the cancer cells look like
normal thyroid cells. 
Within the differentiated thyroid cancers there are two types of cancer that you’ll
have to know for your exams: papillary carcinoma and follicular carcinoma. 
Now, papillary carcinomas are the most common form of thyroid cancer and this is
high yield! 
Thankfully they have an excellent prognosis. 
They are associated with RET/PTC rearrangements and BRAF gene mutations as
well as exposure to ionizing radiation during childhood. 
The name “papillary” refers to the fact that these tumors have finger-like
prolongations of follicle cells known as papillae that tend to grow slowly towards
nearby lymphatic vesselsand invade nearby lymph nodes in the neck. 
Under the microscope, the nuclei of papillary carcinomas cells contain very few
proteins and a small amount of DNA, and that gives the appearance of an empty
nucleus, sometimes called an “Orphan Annie eye” nucleus based on an old famous
cartoon character. 
Another feature are psammoma bodies, which are calcium deposits within the
papillae and you absolutely have to remember this for your exams. 
The second type, follicular carcinomas, represent the second most common form
of thyroid cancer and they have a good prognosis. 
This type of thyroid cancer is associated with the activation of RAS oncogene and
PAX8-PPAR-gamma translocations which promotes proliferation. 
In follicular carcinomas, the tumor develops from the follicular cells and grows until it
breaks through the fibrous capsule. 
Unlike papillary thyroid carcinomas, from there, follicular carcinomas can invade into
nearby blood vessels and spread to other parts of the body. 
So moving beyond the differentiated thyroid cancers, there are
medullary thyroidcarcinomas which arise from C-cells. 
Most of the time, it forms because of a spontaneous mutation in the RET oncogene,
and it’s usually a single carcinoma in one lobe of the thyroid. 
Another high yield fact is that it’s associated with a hereditary condition
called multiple endocrine neoplasia, or MEN, type 2A and 2B. 
In these conditions, one or more of the endocrine glands like the thyroid
gland, parathyroid gland, and adrenal gland develop tumors. 
Under the microscope, medullary thyroid carcinoma is made up of spindle-shaped
cells, which are called that because they’re long and skinny , like a spindle that’s
used to spin fibers into thread. 
C-Cells in the tumor make excessive amounts of calcitonin which deposits between
the C-Cells. 
As the calcitonin deposits, the resulting clumps of protein stick together and form
fibrous deposits called amyloid around the C-cells, which can be seen with Congo
red stain. 
Finally, there are the anaplastic thyroid carcinomas which are associated with
mutations in the TP53 tumor suppressor gene. 
Anaplastic thyroid carcinomas are rare form of thyroid cancer that usually appears in
older individuals and has a poor prognosis. 
The altered cells don’t look anything like normal thyroid cells. 
It may be that these tumors derive from an existing papillary or follicular cancer
where the cells mutate even more and become unrecognizable. 
They often grow beyond the fibrous capsule of the thyroid gland and invade nearby
structures.
Most often the first sign of thyroid cancer is a solitary painless nodule in the thyroid
gland. 
Typically, hard and immovable nodules are more likely to be tumors. 
If the tumor gets too big or invades the larynx or esophagus, it can
cause hoarseness and trouble swallowing. 
Although thyroid adenomas can sometimes cause hyperthyroidism, thyroid
cancers are non functional so they usually do not present with signs
of hyper or hypothyroidism. 
The diagnosis of thyroid cancer often begins with imaging studies, like
a thyroidultrasound, which can help identify a thyroid nodule. 
Calcitonin levels are usually elevated in medullary thyroid carcinomas. 
A radioiodine scan can also be useful, that’s where radioactive iodine is ingested and
taken up by cells that make thyroid hormone. 
Usually, thyroid tumors don’t make thyroid hormone, so they appear as “cold
nodules”. 
The diagnosis of thyroid cancer is usually confirmed by doing a fine-needle
aspiration, where a thin needle is used to take small tissue samples from the thyroid
nodule. 
Treatment often involves partial thyroidectomy, after which complications can
appear: 
First, there can be hypothyroidism if a large portion of the organ is removed. 
Hoarseness can occur due to damage to the right recurrent laryngeal nerve which
innervates most of the muscles in the larynx. 
There could also be damage to the external branch of the superior laryngeal nerve
that innervates the cricothyroid which can prevent the person from raising the pitch
of their voice. 
Hypocalcemia can also occur due to removal of the parathyroid glands. 

Summary
Alright, as a quick recap, Thyroid adenomas are benign and solitary growths on
the thyroid. 
Most often they are non-functional but in rare cases, can cause hyperthyroidism. 
Next there are three main types of thyroid cancer: differentiated, medullary,
and anaplastic. 
Differentiated thyroid carcinomas arises from follicular cells. 
The most common are papillary carcinomas and they are associated with RET/PTC
rearrangements and BRAF gene mutations as well as exposure to ionizing
radiation during childhood. 
On histology, there are “Orphan Annie eye” nucleus and psammoma bodies. 
The second is follicular carcinomas which are associated with the activation of RAS
oncogene and PAX8-PPAR-gamma translocations. 
Moving beyond the differentiated thyroid cancers, we have
medullary thyroid carcinomaswhich arise from C-cells and are often associated with
RET mutations and MEN type 2A and 2B. 
Finally, there are the anaplastic thyroid carcinomas. 
These are a rare form of thyroid cancer that usually appears in older individuals and
are associated with TP53 mutations. 
The diagnosis of thyroid cancer is done with fine-needle aspiration and treatment
often involves thyroidectomy. 
Back to our cases. 
Dasha came in with a lump in her neck and echography confirmed that it was a
cold thyroid nodule. 
After doing a fine needle aspiration, histology showed, empty appearing nuclei with
central clearing, the so-called “Orphan Annie eyes” and psammoma bodies. 
Her history of living close to Chernobyl, by that we need that she may have been
irradiated, plus histology suggests that she has papillary carcinoma. 
Mike also came in with a cold thyroid nodule, but in this case, histology
showed spindle-shaped cells and amyloid around C-cells. 
His family history of MEN type 2A and histology suggests medullary carcinoma. 
If genetic testing were to be done, it will probably show RET gene mutations.

Skin cancer
Skin cancer is an uncontrolled growth of cells within the skin. 
There are three main types: basal cell carcinoma, squamous cell carcinoma,
and melanoma. 
Some skin cancers can spread to other locations in the body and can be fatal, as
seen with singer-songwriter Bob Marley, who died shortly after being diagnosed
with melanoma.
The skin is divided into three layers--the epidermis, dermis, and hypodermis. 
The hypodermis is made of fat and connective tissue that anchors the skin to the
underlying muscle. 
Just above is the dermis, which contains hair follicles, nerves and blood vessels. 
And just above that, the outermost layer of skin, is the epidermis. 
The epidermis itself has multiple cell layers that are mostly keratinocytes - which are
named for the keratin protein that they're filled with. 
Keratin is a strong, fibrous protein that allows keratinocytes to protect themselves
from getting destroyed, when you rub your hands through the sand at the beach. 
Keratinocytes start their life at the deepest layer of the epidermis called the stratum
basale, or basal layer, which is made of a single layer of small, cuboidal to low
columnar stem cellsthat continually divide and produce new keratinocytes that
continue to mature as they migrate up through the epidermal layers, flattening out to
a pancake-like squamous shape as they ascend.
But the stratum basale also contains another group of cells - melanocytes, which
secrete a protein pigment, or coloring substance, called melanin. 
Melanin is actually a broad term that constitutes several types of melanin found in
people of differing skin color. 
These subtypes of melanin range in color from black to reddish yellow and their
relative quantity and rate at which they are metabolized define a person’s skin color. 
When keratinocytes are exposed to the sun, they send a chemical signal to
the melanocytes, which stimulates them into making more melanin. 
The melanocytes move the melanin into small sacs called melanosomes, and these
get taken up by newly formed keratinocytes, which will
later metabolize the melanin as they migrate into higher layers of the epidermis. 
Melanin then acts as a natural sunscreen, because its protein structure dissipates, or
scatters, UVB light--which if left unchecked can damage the DNA in the skin cells
and lead to skin cancer. 
Melanocytes can also be found in the dermis, at the base of the hair follicle, where
they transfer melanin to the keratinized cells that make up hair. 
Now, a tumor develops if there’s a DNA mutation in any of these cell types that leads
to uncontrolled cell division. 
Typically these are mutations in proto-oncogenes which result in a promotion of cell
division, or mutations in tumor suppressor genes which result in a loss of inhibition of
cell division. 
You can think of proto-oncogenes as the accelerator or gas pedal and tumor
suppressor genes as the brakes. Too much acceleration or an inability to brake can
lead to runaway cell division. 
As a result, the mutated cells can start piling up on each other and can become a
tumor mass. 
Some of these tumors are benign and stay well contained or localized. But some
become malignant tumors or cancers, and these are the ones that break through
their basement membrane and invade nearby tissues. 
Malignant tumor cells can get into nearby blood or lymph vessels, and travel from the
primary site to establish a secondary site of tumor growth somewhere else in the
body - and that’s called metastasis.
Skin cancer is differentiated based upon the type of skin cell that’s involved in the
tumor mass. 
The most common is basal cell carcinoma, which involves cells in the stratum
basale. These tend to be slow growing tumors that can be locally invasive, but rarely
metastasize to distant regions of the body.
Nearby blood vessels in the dermis can become dilated to deliver more nutrients as
the tumor grows. 
Basal cell carcinomas can grow superficially, spreading over several centimeters of
the epidermis. And they can break through the basement membrane and invade
the dermis, forming islands or cords of tumor cells. 
Tumor cells on the periphery of islands typically arrange themselves in a line, like
fence-posts, forming a palisading pattern. 
The second most common type of skin cancer is squamous cell carcinoma which
involves squamous keratinocytes. 
Now, a precancerous lesion that can turn into squamous cell carcinoma is
called actinic keratosis. 
In an actinic keratosis, keratinocytes are damaged by radiation and begin to over-
produce keratin. 
Over time, these damaged keratinocytes can develop into squamous cell carcinoma.
An early stage of squamous cell carcinoma is also called Bowen’s disease
or squamous cell carcinoma in situ. 
At this point, the tumor can be found in the epidermis, but it has not broken through
the basement membrane. Tumor cells are atypical – enlarged and over pigmented.
As squamous cell carcinoma becomes more invasive, it can break through the
basement membrane and extend into the dermis. It may even reach the hypodermis,
at which point it is more likely to metastasize. 
Tumor cells at these more advanced stages typically vary in their degree of maturity,
have abnormal shapes, and over-produce keratin forming ‘pearls’. 
Finally, the most aggressive form of skin cancer is melanoma which
involves melanocytes.
Now, melanocytic nevus, more commonly known as a mole, results from a type
of melanocyte that over-produces melanin. 
These moles can be considered precancerous because they carry an increased risk
of becoming a melanoma. 
Melanomas grow horizontally within the epidermis and superficial dermis; and they
grow vertically - invading the dermis.
Metastasis is most associated with the depth of invasion, and in fact, melanoma is
the most deadly form of skin cancer because of its tendency to metastasize quickly. 
Typically, the tumor cells have a large nuclei with irregular contours, and
produce melanin in a variety of colors: brown, red, dark blue, and gray.
The causes of skin cancer can be both genetic and environmental.
By far, the leading environmental factor is UV exposure from the sun or tanning
booths. Often, the risk of developing skin cancer increases as sun exposure over a
lifetime accumulates. 
Some viral infections, like human papillomavirus; immunosuppression; and
having light skinalso tend to increase risk. 
Skin cancer typically appears on skin that’s exposed to the sun. 
Basal cell carcinomas can appear as well-circumscribed, pearly, waxy, or
shiny solidelevation of skin. They can also be ulcerated and red or pigmented. 
Actinic keratosis can appear as dry, rough, almost sandpaper-like patches that are
surrounded by tan, brown, red or flesh colored skin. They tend to commonly form on
the lips, face, scalp, arm, ears, and the back of the hands. 
Squamous cell carcinoma can appear as small, well-circumscribed, red elevations of
the skin with scaly plaques on top, which can sometimes ulcerate.
Moles can appear as small; oval; tan, pink, black, or brown spots that can be flat or
elevated. 
Finally, the worrisome signs of melanoma can be remembered using the mnemonic
ABCDE where lesions are asymmetrically shaped, borders are irregular or notched,
coloration varies within the same lesion, the diameter is larger than the size of a
pencil eraser, and the lesion rapidly evolves over time and can cause skin elevation.
These lesions may also be itchy or painful.
A tissue biopsy is needed to make a definitive diagnosis of skin cancer, and
treatment options include removal with surgery or with cryotherapy, where the tumor
is frozen off. Radiation, chemotherapy or immunotherapy may also be options. 
And precancerous cells, like in actinic keratosis or melanocytic nevus, are typically
removed to prevent their progression to skin
cancer with cryotherapy or photodynamic therapy, which is where light is used to
induce cellular death. 

Summary
So, to recap: there are three main types of skin cancer: the most common, basal cell
carcinoma; the second most common, squamous cell carcinoma; and the most
deadly, melanoma – and they all form from uncontrolled growth of cells within the
epidermal layer of the skin. 
Tumors can remain relatively contained, or invade other layers of the skin.
The deeper the tumor invades, the greater the risk of metastasis. 
UV exposure is a risk factor, so areas of the face and body exposed to the sun are
particularly affected, like the scalp; lips; ears; arms; and the backs of the hands. 
Diagnosis is made with a tissue biopsy and treatments can include physically
removing cells with a high risk of developing into skin cancer. 
Tumor cells are also commonly removed and treated with radiation, chemotherapy,
or immunotherapy.
Breast cancer
64-year-old Cassie comes to the office because of a new breast mass that she found
on her monthly self-examination. 
A mammogram shows microcalcification clusters so an excisional biopsy is
performed. 
Pathology shows high-grade cells with central necrosis in the lumen and dystrophic
calcification in the center of the ducts without invasion of the basement membrane. 
Later that day, a 58-year-old named Linda comes to the physician's office
with eczematousdermatitis of the left nipple and areolar area for the past 24 months. 
Her history reveals that the lesion has been treated unsuccessfully
with topical steroidsand has progressively distorted the nipple, resulting
in nipple inversion. 
Physical examination reveals scaly, crusted, and deformed left nipple with multiple
plaques overlying the surrounding areola. 
At first glance, you'd think Cassie and Linda have nothing in common, but the fact is,
they have different forms of breast cancer! 
Breast cancer is the most common malignancy in women and it’s typically seen
in postmenopausal women, over 50 years of age. 
Most breast cancers are adenocarcinomas and they typically arise from
the terminal duct lobular units. 
Breast cancer can present as a palpable hard mass, most commonly located in the
upper outer quadrant of the breast. 
Now, some breast cancers can be associated
with amplification and overexpression of genes
for estrogen receptors, progesterone receptors, and HER2/neu receptors. 
For your exam, you have to remember that these receptors are
important therapeutic and prognostic factors of breast cancer. 
In other words, breast cancers that are associated with overexpression of estrogen
and progesterone receptors are more susceptible to anti-estrogen medications, such
as tamoxifen. 
On the other hand, HER2/neu receptors, also known as erbB2 receptors, are coded
by the ERB-B2 gene. 
These receptors are transmembrane glycoproteins with tyrosine kinase activity that
plays an important role in epithelial growth and differentiation. 
HER2/neu receptors are present in small amounts in normal breast
and ovarian cells; while they are overexpressed in 25-30% of breast cancers as well
as in adenocarcinomas of the ovary, lung, stomach, and salivary glands.
Moreover, breast cancers that are associated with HER2/neu positivity are linked to
more aggressive tumors; however, they are more likely to respond to anti-HER-
2 monoclonalantibodies, like trastuzumab. 
Another high-yield fact is that breast cancers that
are estrogen negative, progesteronenegative, and HER2/neu negative, or in other
words, triple-negative, are linked to a more aggressive form of breast cancer. 
Finally, breast cancer tends to metastasize first to the axillary lymph nodes, while in
the later stages, the most common sites of metastases include lungs, liver, and
bones. 
Now, switching gears and moving on to risk factors! 
The most common risk factors in females include advanced age and family history
of breast cancer, which is considered the strongest risk factor. 
The risk of hereditary breast cancer is increased even more in young women who
have had more than one close relative with premenopausal breast cancer. 
Also, a family history of ovarian cancer is linked to an increased risk
for ovarian and breast cancer, because both of these cancers are associated
with autosomal dominant mutations of BRCA1 and BRCA2 genes. BRCA genes
codes for BRCA proteins that acts as a tumor suppressor that controls the cell cycle,
helps repair DNA, and regulates transcription of DNA. 
Moreover, women with the BRCA1 mutation have a 70-80% higher risk for
developing breast cancer; and a 40% increased risk for developing ovarian
cancer compared to women without the BRCA1 mutation. 
Another commonly high yield factor on your exam is increased estrogen exposure
like nulliparity, late first pregnancy, early menarche, and late menopause. 
Other risk factors include alcohol consumption, absence of breastfeeding,
and obesity in postmenopausal women. 
Remember that after menopause, estrogen levels typically drop, but adipose
tissueconverts androstenedione to estrone, which is a weak estrogen. 
Finally, you shouldn’t forget the influence of race in breast cancer: 
Caucasians are at the highest risk while people of African descent are at increased
risk for the development of triple-negative breast cancer. 
Alternatively, risk factors for breast cancer in men include BRCA2 mutation
and Klinefelter syndrome. 
In terms of screening and diagnosis, according to the American Cancer Society
guidelines, women aged 45-54 years should also undergo
screening mammography every year. 
If a breast mass is palpated during physical exam, a woman should
undergo mammography which is the initial imaging technique used for palpable
breast lesions in women older than 35 years. 
Clinicians can also use needle biopsy to evaluate suspicious breast lesion since this
is the most specific diagnostic tool.
As far as the treatment goes, breast cancer is treated with surgery, radiation therapy,
and systemic therapy. 
Surgical management of breast cancer can be performed as a radical mastectomy,
which stands for removal of one or both breasts; or breast-conserving, which stands
for removal of cancerous tissue while avoiding mastectomy. 
Chemotherapy agents include trastuzumab, a monoclonal antibody against HER-
2/neu receptors and tamoxifen, which is a selective estrogen receptor modulator. 
Finally, aromatase inhibitors like anastrozole can also be used to treat estrogen
receptorpositive breast cancers in post manupausal individuals. 
Now breast cancer can be subdivided into non-invasive and invasive breast
cancers. 
First, let’s start with non-invasive breast cancers. 
Now, remember that at the time when they are found, they have not crossed the
basement membrane and invaded other tissue. 
These include ductal carcinoma in situ, Paget disease of the breast, and lobular
carcinoma in situ. 
Ductal carcinoma in situ, or DCIS, is a precancerous lesion characterized by a mass
of neoplastic cells that arise from epithelial cells in the terminal duct lobular unit. 
As they proliferate, neoplastic cells fill the lumen of the duct, but at the same time,
they do not invade into the basement membrane, which is why they are “in situ”. 
In most cases, DCIS affects only one ductal system; but in some individuals, it can
present as a more extensive lesion that spread to surrounding breast tissue. 
In addition, DCIS accounts for 15-30% of all carcinomas found on
screening mammograms; and 50% of all carcinomas identified on
diagnostic mammograms. 
Now there are two subtypes of ductal carcinoma in situ: comedo DCIS and non-
comedoDCIS. 
Comedo DCIS, also referred to as comedocarcinoma, is associated with solid sheets
of pleomorphic, high-grade malignant cells, which indicate that this cancer is growing
rapidly. 
Moreover, central malignant cells can die and result in central necrosis, which can
eventually calcify and form dystrophic calcifications. 
Additional findings can include chronic inflammation and periductal
concentric fibrosis. 
Finally, if left untreated, malignant cells can eventually penetrate the basement
membrane and invade the surrounding breast tissue, forming a poorly defined
palpable breast nodule. 
So for your exam, you have to remember that comedocarcinoma typically does not
produce a mass lesion unless it has invaded the surrounding breast tissue; instead,
it’s most commonly identified as microcalcification clusters on mammography. 
In contrast to comedo DCIS, non-comedo DCIS is not associated with central
necrosis and it’s subdivided into three types: papillary and micropapillary DCIS,
which are characterized by malignant cells that are arranged in a finger-like pattern
within the duct; cribriform DCIS, which is characterized by gaps between malignant
cells; and solid DCIS, where cancer cells completely fill the duct. 
The next non-invasive breast malignant condition is Paget disease of the breast! 
Paget disease occurs when ductal carcinoma, either in situ or invasive, extends up
to the lactiferous ducts and into the nipple and areola. 
So, you have to know that women with this condition typically present with
an eczematousskin lesion or persistent dermatitis in the nipple and adjacent areas. 
The diagnosis of Paget disease of the breast is established by obtaining a biopsy,
but women with Paget disease must undergo mammography to detect the presence
of underlying breast cancer. 
Histologically, Paget disease of the breast demonstrates Paget cells, which are
intraepithelial adenocarcinoma cells. 
As far as the treatment goes, the initial management of Paget disease of the breast
is a mastectomy. 
In addition, Paget disease of the breast that is positive to estrogen receptors can be
treated using an estrogen receptor antagonist like tamoxifen. 
Finally, there’s lobular carcinoma in situ, or LCIS, which arises in lobules and acini of
the terminal duct lobular unit. 
LCIS is not associated with the classic presentation of breast cancers, such as a
palpable breast lesion, radiological features, or microcalcifications; instead, it’s most
commonly diagnosed as an incidental finding on biopsy for some other mass lesion,
such as fibroadenoma. 
Finally, for your exam, you have to remember that LCIS is associated with an
increased risk of breast cancer developing in both breasts, in contrast to DCIS,
where the risk is increased in the affected breast. 
Now, switching gears and moving on to invasive breast cancers, which typically
present as a poorly-defined, firm, palpable breast mass or a mammographic finding. 
As cancer invades surrounding breast tissue, it can infiltrate pectoral muscles and
deep fascia, thereby form immobile masses. 
Moreover, infiltration of the central region of the breast can lead to nipple retraction,
while the invasion of the suspensory Cooper ligaments leads to retraction of the
overlying skin. 
Finally, if the cancer cells obstruct the dermal lymphatics, they can
cause lymphedema and thickened skin around exaggerated hair follicles, eventually
giving the skin the appearance of an orange peel, also referred to as peau
d'orange finding. 
Invasive breast cancers include invasive ductal breast carcinoma, invasive
lobular breast carcinoma, medullary breast carcinoma, and inflammatory breast
carcinoma. 
First, let’s focus on invasive ductal carcinoma, which is the most commonly
diagnosed type of invasive breast cancer. 
Typically, it arises from the terminal duct lobular unit and presents as a unilateral
firm, fibrous, rock-hard palpable breast mass with sharp margins. 
In advanced stages, invasive ductal carcinoma can cause skin dimpling
or nipple retraction. 
Histologically, it’s characterized by small glandular cells in the stroma, and it can be
tubular or mucinous. 
Tubular carcinoma is characterized by well-differentiated tubular structures that lack
myoepithelium; while mucinous carcinoma is associated with malignant cells that are
scattered throughout abundant extracellular mucin. 
For your exam, you should remember that the mucinous subtype is most commonly
seen in older women after they’ve gone through menopause. 
Finally, invasive ductal carcinoma has a tendency to metastasize via the lymphatic
vesselsand it’s also the most common type of breast cancer in males. 
Moving on to invasive lobular breast carcinoma! 
This is the second most common type of invasive breast cancer. 
It’s often associated with lobular carcinoma in situ. 
In contrast to invasive ductal carcinoma, invasive lobular carcinoma is often bilateral
with multiple lesions in the same location that are not palpable on breast
examination. 
A high yield fact is that this tumor is associated with low E-cadherin expression,
which is a gene that codes adhesion proteins that prevent cancer cells from
spreading into the surrounding breast tissue. 
Histologically, invasive lobular carcinoma is characterized by cancer cells that are
clustered into strands or chains that invade into the adjacent stroma. 
Remember: Lines of cells are associated with invasive Lobular carcinoma. Also,
there’s no duct formation. 
The next one is medullary carcinoma, which is a type of breast cancer that most
commonly presents as a well-circumscribed palpable mass that can mimic benign
lesions, such as fibroadenoma. 
Medullary carcinoma is more common in younger women and it’s associated with
BRCA1 mutation and triple-negative phenotype. 
Histologically, it’s characterized by large anaplastic cells that grow in sheets
and infiltrateof lymphocytes and plasma cells. 
Finally, there’s inflammatory breast carcinoma, which often affect women younger
than 40. 
Women with inflammatory breast carcinoma commonly present with peau
d'orangefinding, breast tenderness, pruritus, warm erythematous skin or skin
discoloration, which can range from pale pink to deep red and purple. 
On physical exam, they can lack a palpable mass, therefore the condition can be
mistaken for mastitis or Paget disease of the breast. 
Inflammatory breast carcinoma is very aggressive and always locally invasive at
the time of diagnosis which gives it a higher stage and a poor prognosis.
Unlike the name would suggest, symptoms are caused by the blockage
of dermallymphatics and not inflammation. 
On histology, there are tumor cells that invade into the dermal lymphatics in the
affected areas. 

Summary
All right, as a quick recap. 
Breast cancer is the most common malignancy in women and it’s typically seen
in postmenopausal women, over 50 years of age. 
Most breast cancers are adenocarcinomas that typically arise from the terminal duct
lobular unit and they can present as an incidental finding on a
screening mammogram or as a palpable breast mass. 
In most cases, they are located in the upper outer quadrant of the breast and they
are evaluated by triple assessment method: clinical examination, imagining methods,
such as ultrasound or mammography, and needle biopsy. 
Next, breast cancers are subdivided into non-invasive breast cancers and
invasive breast cancers. 
Non-invasive breast cancers include DCIS, which is further subdivided
into comedo and non-comedo DCIS; Paget disease of the breast; and LCIS. 
On the other hand, invasive breast cancers include invasive ductal
carcinoma, invasive lobular carcinoma, medullary breast carcinoma, and
inflammatory breast carcinoma. 
Finally, the treatment of breast cancer includes surgical management, such
as radical mastectomy or breast-conserving surgery; radiation therapy; and
chemotherapy. 
If the breast cancer is estrogen receptor positive, they will respond to treatment with
anti-estrogen medications like tamoxifen, which is a selective estrogen receptor
modulator, or aromatase inhibitors like anastrozole. 
If it’s HER-2/neu receptor positive, it will respond to trastuzumab,
a monoclonal antibody against HER-2/neu receptors. 
And that’s not all! 
Here’s an overview of the most common benign and malignant breast conditions and
parts of the breast that they affect! Feel free to pause the video.
Now, let’s go back to our case! 
First, there was Cassie who noticed a new breast mass on her monthly self-
examination. 
A mammogram showed microcalcifications clusters so excisional biopsy was
performed which showed high-grade cells with central necrosis and dystrophic
calcifications. 
Since there was no invasion of the basement membrane, we can say that this is a
classic presentation of ductal carcinoma in situ, more specifically comedocarcinoma! 
On the other hand, Linda complained about chronic eczematous dermatitis of the
left nipple and areolar area for the past 24 months. 
Her history revealed that the lesion was treated unsuccessfully
with topical steroids and physical examination showed scaly, crusted, and deformed
left nipple with multiple plaques overlying the surrounding areola. 
Linda must undergo mammography and detect the possible presence of
underlying breast cancer. 
She most likely has Paget disease of the breast. 
A biopsy is needed to confirm the presence of Paget cells and to rule out
inflammatory breast carcinoma.

Vaginal cancer
Vaginal cancer is a rare gynecologic malignancy. 
The most frequent histologic subtype is squamous carcinoma, which develops from
the squamous epithelium of the vagina, in which case, it's in relation to an HPV
infection, particularly high risk strains, like HPV 16 and 18. 
Sometimes, however, clear cell adenocarcinoma can occur, which develops from the
glandular cells of the vagina, in which case it’s almost always because of exposure
to a medication called diethylstilbestrol, or DES for short. 
So, risk factors for vaginal cancer depend on the histologic subtype. 
For vaginal squamous cell carcinoma, they’re the same as for cervical cancer:
multiple lifetime sexual partners, early age at first sexual intercourse, as well as
smoking, and immunocompromising conditions, like an HIV infection.
For vaginal adenocarcinoma, the only known risk factors are in utero exposure to
DES. 
This medication was prescribed to females between 1940 and 1970 to prevent
pregnancy complications, like miscarriage - so their daughters would be at risk for
developing vaginaladenocarcinoma.
Most of the time, vaginal cancer is asymptomatic. 
If there are symptoms, abnormal postcoital or postmenopausal vaginal bleeding are
the most common ones, and a watery, blood-tinged or foul-
smelling vaginal discharge may be present as well. 
In later stages, when the cancer has spread further than the vagina, pelvic pain may
be present. 
When the bladder is involved, there may also be symptoms like urinary frequency,
and if the cancer has spread to the rectum, there may be constipation. 
The speculum examination can usually identify any suspicious or abnormal looking
masses inside the vagina, most commonly located on the upper third of the
posterior vaginal wall. 
Most commonly, vaginal cancer looks like a mass, but it can also look like a plaque
or an ulcer. 
In addition, if there are enlarged inguinal lymph nodes, that may be a sign of
metastatic disease. 
If a mass is visible in the vagina, a biopsy should be obtained.
If not, a vaginal cytology specimen should be obtained. 
Results can be negative for intraepithelial lesions or malignancy, or NILM for short,
or show varying degrees of atypia in the vaginal epithelial cells. 
For example, some results come back as atypical squamous cells. 
Atypical squamous cells look mildly atypical, and don’t necessarily develop
into vaginal cancer, and they can further be classified as either ASC-US, where US
stands for unknown significance, and there are no high grade intraepithelial lesions,
or ASC-H, which is when there may be a high grade intraepithelial lesion and further
testing is recommended. 
Alternatively, the result may come back positive for intraepithelial lesions, which can
be either low grade squamous intraepithelial lesions, or LSIL, or high grade
squamous intraepithelial lesions, or HSIL, depending on how dysplastic the cells
look. 
Frequently, HPV genotyping is also performed - meaning the vaginal cytology
sample is analyzed for the presence of high risk HPV DNA. 
ASC-US and LSIL results can be followed-up by repeating the vaginal cytology once
a year for two years in a row, until two NILM results come back. 
Alternatively, vaginal cytology and HPV genotyping may be repeated in one year,
and if they come back as NILM with negative HPV genotyping, screening can be
stopped. 
A vaginal colposcopy is recommended from the get-go if vaginal cytology shows
HSIL, ASC-H, or if high risk HPV is genotyping is positive at any test, initial or during
follow-up, or if any result comes back as ASC-US or worse during the follow-up
period. 
Now, a colposcopy is done with a magnifying device called a colposcope to get a
zoomed in view of the vagina, in order to obtain biopsies from suspicious looking
areas. 
To better highlight abnormal cells, different solutions, like 3 to 5% acetic acid, or
dilute Lugol solution may be applied, which makes abnormal cells change color. 
During colposcopy, biopsies should be obtained from the transformation zone, and
from any other suspicious-looking areas - like those that become white after acetic
acid staining. 
Now, the biopsy results can differentiate squamous cell carcinoma from clear cell
adenocarcinoma. 
For squamous cell carcinoma, the biopsy can also distinguish between precancerous
lesions, like vaginal intraepithelial neoplasia, or invasive vaginal cancer. 
Vaginal intraepithelial neoplasia, or VaIN for short, is classified depending on how
much of the vaginal epithelium is affected. 
VaIN 1 is when only the lower one third of the epithelium is made up of atypical cells,
VaIN 2 is when the lower two thirds are affected, and VaIN 3 involves more than two
thirds of the epithelium. 
Carcinoma in situ is when the entire epithelium is made up of atypical cells, and it’s
included in the VaIN 3 category. 
Finally, invasive vaginal cancer is when the cancer cells have breached through the
basement membrane. 
VaIN 1 lesions are managed conservatively, as they don’t always progress to
cancer, and they tend to regress and recur in other places spontaneously or after
treatment. 
VaIN 2 or 3 lesions should be removed - and usually that’s done through surgical
excision. 
Depending on the degree of excision, the procedure can be local excision, a partial
vaginectomy, or a total vaginectomy, for extensive disease.
For early lesions, other options include ablation with a carbon
dioxide laser, topical therapy with agents like imiquimod, or radiation of lesions. 
Invasive vaginal cancer is further staged with a CT or MRI to determine the primary
tumor size, local extension, and lymph node involvement, and a chest and
skeletal X-ray are also done - as vaginal cancer loves to metastasize to the lungs
and bones.
Stage I vaginal cancer is confined to the vagina, and there are no lymph node or
distant metastases. 
Stage II is when the cancer has grown through the vaginal wall, but hasn’t reached
the pelvic wall, and there are no lymph node or distant metastases. 
Stage III is when the cancer has grown into the pelvic wall, or spread to the lower
one third of the vagina, or has blocked the flow of urine, causing hydronephrosis,
and there may or may not be distant metastases. 
And finally, with stage IV cancer, there are distant metastases. 
No matter the histologic subtype, treatment for stage I tumors is surgical excision,
involving a radical hysterectomy, an upper vaginectomy, and bilateral pelvic
lymphadenectomy. 
For stages II through IV, treatment is done with chemoradiation, meaning both
chemotherapy and radiation therapy are done. 
Usually, a chemotherapeutic regimen based on 5-fluorouracil with or
without cisplatin is chosen. 

Summary
Alright, as a quick recap...Vaginal squamous cell carcinoma amounts for 90%
of vaginalcancers, and it arises because of an infection with high-risk HPV strains
like 16 and 18. 
Vaginal adenocarcinoma, on the other hand, is related to in utero exposure
to diethylstilbestrol. 
When there’s a vaginal mass, a biopsy is done. 
When there is no mass, vaginal cytology can be done.
ASC-US and LSIL results can be followed-up by repeating the vaginal cytology once
a year for two years in a row, until two NILM results come back. 
Alternatively, vaginal cytology and HPV genotyping may be repeated in one year,
and if they come back as NILM with negative HPV genotyping, screening can be
stopped.
A vaginal colposcopy and a biopsy is recommended from the get-go
if vaginal cytology shows HSIL, ASC-H, or if high risk HPV is genotyping is positive
at any test, initial or during follow-up, or if any result comes back as ASC-US or
worse during the follow-up period. 
The biopsy can come back as VaIN 1, 2, 3 or invasive vaginal cancer. 
VaIN 1 lesions are managed conservatively. 
VaIN 2 and 3 lesions can be surgically removed, or treated
with ablation, topical therapy or radiation. 
Stage I invasive vaginal cancer is treated with a radical hysterectomy, an upper
vaginectomy, and bilateral pelvic lymphadenectomy, and stages II through IV are
treated with chemoradiation.

Oral cancer
Oral cancer describes cancers that originate in the oral cavity. 
The oral cavity includes the lips, the gingiva, or gums, the floor of the mouth,
the buccal mucosa which is the soft lining of the inner lips and cheeks, the anterior or
front two-thirds of the tongue, the hard palate which is the tough front part of the roof
of the mouth, and the retromolar trigone which is the mucosa right behind the
last molars on the bottom row of teeth. 
Behind the oral cavity is the oropharynx. 
The oropharynx includes the soft palate which is the soft part of the roof of the mouth
right behind the hard palate, the tonsils, the walls of the throat, and the posterior or
back one-third of the tongue. 
The oral cavity and oropharynx are lined by epithelium - and there are a few different
types.
The first type of epithelium is called keratinized stratified squamous epithelium. 
These epithelial cells produce keratin, a protein that makes the layer tough, and
protects against normal wear and tear from food and drinks.
Beneath the epithelium, there's another layer called the basement membrane made
of tough connective tissue, and below that is the lamina propria which yet more
connective tissue that houses blood vessels, lymphatics, nerves, and immune cells. 
The oral surfaces covered in keratinized epithelium include the hard palate, the
dorsal surface, or top, of the tongue, and the gingiva.
A second type of epithelium is non-keratinized stratified squamous epithelium, and it
contains cells that don’t produce much keratin, making this layer less tough. 
The oral surfaces covered by non-keratinized stratified squamous epithelium include
the buccal mucosa, the floor of the mouth, the lateral and ventral, or bottom,
surfaces of the tongue, the soft palate, and the retromolar trigone.
Now the mucosal tissue in the oral cavity can undergo
several premalignant pathological changes.
The first one of these is leukoplakia, where leuko- means white and -plakia means a
flat, raised patch or plaque. 
And leukoplakia specifically relates to a white plaque with no clear underlying cause. 
These leukoplakias are usually painless but can’t be easily scraped away. 
Now, the exact cause for leukoplakia is unknown, but a known risk factor is tobacco
use. 
Early on, these lesions are usually pretty thin, so it’s called thin leukoplakia. 
These can either go away on their own, remain unchanged, or grow and become
thicker, at which point it’s called thick leukoplakia. 
If it becomes bumpy it’s called nodular leukoplakia, and if it becomes wart-like it’s
called verrucous leukoplakia. 
Now a more serious form of leukoplakia is called proliferative verrucous leukoplakia,
which usually affects women, with no risk factors and it has a predilection
for gingiva and causes multiple rough white lesions that grow and spread, and in
most cases, eventually develop into squamous cell carcinoma. 
At the cellular level, leukoplakia typically shows a thickened keratin layer.
Since keratin absorbs water, a thick keratin layer looks white when it’s wet. 
At a cellular level, leukoplakia may show cells that have undergone some degree
of dysplasia, meaning they look abnormal in some way, but are not cancerous, or
malignant, yet.
However, leukoplakia is considered a precancerous condition, meaning that
compared to normal tissue, it’s more likely to develop into a cancer in the future. 
And that change could happen at the microscopic level, meaning that the lesion
might look the same on the outside, even though the cells have become cancerous. 
Generally speaking, the transition from dysplastic cells to malignant cells occurs
gradually. 
And as cells become more and more dysplastic the lesions sometimes develop red
spots, and at that point it’s called erythroleukoplakia. 
Cells in these red areas have suffered serious damage to their DNA and don’t
mature normally and therefore can’t produce keratin. 
And as they become more and more atypical, the more immature becomes the
epithelium and it will start becoming thinner or atrophic and allow more of the
underlying blood vessels to be seen through the mucosa.
At that point the lesion will be completely red and will be called erythoplakia. 
Erythroplakias are more serious than leukoplakia because almost always when they
are removed and examined under the microscope they will show severe dysplasia,
or early cancer. 
Now, a lesion that looks like leukoplakia, but isn’t, is an area of frictional keratosis. 
That’s where there’s repeated physical trauma like rubbing of the tooth surface
against the mucosa of the cheeks.
For example, after a dental procedure that leaves a rough tooth surface, or a
broken toothrubbing against the mucosa.
It’s a normal hyperplastic response, meaning the epithelial cells in the area divide
more than usual and build up a protective layer of keratin.
It’s a bit like developing a callus on your hands after spending the weekend
raking leaves.
An area of frictional keratosis is not a precancerous lesion and usually fades away
once the irritation stops.
Most of the oral cavity is lined by stratified squamous epithelium, so the majority of
cancers that arise are squamous cell cancers.
Squamous cell cancers arise from squamous cells that undergo genetic mutations
that either activate proto-oncogenes or inactivate tumor suppressor genes.
When proto-oncogenes, like epidermal growth factor receptor and ras, are activated,
it turns them into oncogenes that promote cell division. 
And when tumor suppressor genes, like the genes that encode proteins p53, p16,
and the retinoblastoma protein, also called pRb, are inactivated, it removes the
inhibition to cell division. 
So together there’s uncontrolled cell division which can give rise to a tumor. 
As the cancer cells divide they can sometimes gain the ability to penetrate through
the basement membrane, and at that point it’s considered a malignant tumor. 
The malignant cells can then invade surrounding tissues like the salivary glands,
muscle, and even get into the blood and lymphatic systems, and metastasize,
or travel, to other areas of the body. 
It’s a bit like a toddler learning to get out of the crib and then running rampant
through the house.
Proliferative verrucous leukoplakia can turn into a particular type of squamous cell
cancercalled verrucous carcinoma, and it’s also sometimes called snuff-dipper’s
cancer since it is more common among users of snuff and other forms
of chewing tobacco.
Generally speaking, malignant cells are irregularly-shaped with darkly staining
nuclei, enlarged nucleoli, and produce abnormal keratin that look like pearls - so
they’re called keratin pearls. 
It’s thought that most of the time, co-carcinogenesis is necessary to cause oral
squamous cell carcinoma. 
That means that more than one carcinogen, or causative factor, is needed to cause
the disease - like abusing alcohol and using tobacco. 
Many carcinogens come into contact with a wide area within the oral
cavity and oropharynx, so the idea is that they cause field cancerization. 
This means that the entire contacted area or field undergoes genetic changes and is
more likely to develop cancer in the future. 
In addition to squamous cell carcinomas other types of oral cancers
include adenocarcinomas, which develop in glandular cells like those of the salivary
glandsbeneath the mucosa, extranodal lymphomas which develop in lymphocytes,
and melanomas, which develop in melanocytes, found all over the mucosal
epithelium, but most often in the hard palate.
Squamous cell carcinoma is also known to arise at the lip vermillion in those
who smoke, right at the location where a person holds the smoking device, such as
a cigarette or pipe. 
However, most lip vermillion cancers result from chronic sun damage and are
associated with actinic cheilitis, a precancerous rough patch on the lip. 
The most common locations for oral cancer are the lateral and ventral surfaces of
the tongue and floor of the mouth, and the lower lip vermilion because it’s exposed to
more sun than the upper lip.
Well known risk factors for oral squamous cancer include tobacco smoking, alcohol
abuse, chewing betel quids or paan, UV radiation, exposure to metal dust or
chemicals like phenoxyacetic acid; vitamin and mineral deficiencies, like a severe
form of iron-deficiencycalled Plummer-Vinson syndrome, and various immune
deficiencies. 
Oropharyngeal cancers are strongly associated with infection by human
papillomavirustype 16, but interestingly, tumors of the oral cavity, like the lateral
tongue and floor of the mouth are not usually associated with HPV 16. 
The symptoms of oral cancer include numbness or changes in sensation in the
mouth and throat, a hoarse voice, pain or difficulty with chewing or swallowing, and
both painless and painful lumps, sores, or discolorations in the mouth that don’t heal.
Signs of precancerous development include areas of leukoplakia, erythroplakia,
erythroleukoplakia or any other abnormal appearing tissue or masses. 
In other words, white or red lesions without an obvious traumatic source and have a
rough, irregular, velvety or speckled surface - are the ones to look out for. As the
tumor grows some become exophytic, where it grows outward, or endophytic, where
it grows inward.
Diagnosis typically includes a biopsy of the tissue because the cancer has to be
confirmed histologically. 
A lymph node biopsy and imaging such as an X-ray, CT, or combination imaging like
a PET/CT might be necessary for tumor staging.
The staging system consists of T, for the primary tumor’s size and involvement of
surrounding structures or muscles; N, for the number and location of involved lymph
Nodes; and M, for Metastasis which denotes whether distant spread of the cancer
has occurred or not.
Generally speaking, the higher the number assigned to either of these components,
the higher the stage, and worse the prognosis.
While the prognosis of squamous cell carcinoma in the oral cavity depends largely
on the tumor stage, HPV status is a main prognostic factor for squamous cell
carcinoma in the oropharynx.
Treatment of precancerous lesions begins with active surveillance, removing
any diseasedtissue, and stopping any causative agents, like smoking and alcohol
abuse.
Malignant lesions are mainly treated by surgery, but some cases also require
chemotherapy, or radiation therapy. 
And ideally, these lesions are caught early so that they can be better managed. 
That’s why it’s important to screen for oral cancers like with a routine head and neck
exam in the dental office. 
That’s where it’s good to look for early lesions which are often red or white plaques
with an unknown cause. 

Summary
All right, as a quick recap... Oral cancer refers to cancers that originate in the oral
cavity, which is lined by keratinized or non-keratinized stratified squamous epithelia.
Leukoplakia is a precancerous white lesion, but more serious lesions include the red-
colored erythroplakia which almost always contain severe dysplasia or early cancer. 
Risk factors for oral cancer include alcohol abuse, tobacco smoking, and using betel
quid, immunodeficiency, and nutritional deficiencies. 
Diagnosis includes a biopsy, while treatment might include surgery, chemotherapy,
or radiation therapy.

Cervical cancer and cervical intraepithelial neoplasia

Cervical cancer is a cancer of the female reproductive system that originates in
the cervix. 
It's one of the most common cancers in women and it’s usually the result of an
infection by the human papillomavirus, or HPV. 
It has also played a huge role in scientific research thanks to cervical cancer cells
from a woman called Henrietta Lacks, which were the first human cells to be grown
in a laboratory and which continue to be used to this day in labs around the world.
The cervix is also called the neck of the uterus, and it protrudes into the vagina.
The interior cavity of the cervix is called the cervical canal and it can be divided into
two sections. 
The endocervix is closer to the uterus, not visible to the naked eye, and it’s lined by
columnar epithelial cells that produce mucus.
The ectocervix is the continuous with the vagina and it’s lined by mature squamous
epithelial cells. 
Where the squamous epithelium of the ectocervix and the columnar epithelium of
the endocervix meet, there’s a line called the squamocolumnar junction. 
And right where the two types of cells meet, there’s the transformation zone - which
is where sub-columnar reserve cells multiply and transform into immature squamous
epithelium through a process called metaplasia. 
Normally, mature cells are stuck in the G1, or Growth 1, phase of the cell cycle,
which is when cells grow take care of regular cellular business, like synthesizing
proteins and producing energy. 
Eventually, whenever new cells are needed, they’ll exit G1 and keep going through
the rest of the cell cycle to eventually divide in two new identical daughter cells.
Sometimes though, cells can be pushed out of G1 and go through the cell
reproduction cycle faster than the body needs new cells. 
This uncontrolled growth and multiplication is called dysplasia and it’s exactly
how cervical cancer develops from precancerous cells. 
Dysplasia in the epithelial layer of the cervix, also called cervical intraepithelial
neoplasia or squamous epithelial lesion, usually starts in the basal layer of the
transformation zone, typically in the immature squamous epithelium there. 
In most cases, cervical intraepithelial neoplasia is caused by an HPV infection. 
There are over 100 different types of HPV, but only about 15 of them have been
linked with cervical cancer. 
Specifically, HPV-16 is responsible for more than half of all cervical cancers. 
The virus is like a house guest that overstays their welcome and starts using the
kitchen to make all their favourite foods: it inserts itself into the immature squamous
cells of the transformation zone and then integrates its DNA into the host DNA. 
Using the host DNA, HPV makes huge amounts of two of its proteins, E6 and E7. 
These proteins are responsible for pushing mature squamous cells through the cell
replication cycle by blocking the action of tumor suppressor genes, like p53. 
The end result is uncontrolled replication of cervical epithelial cells which are
resistant to apoptosis, or normal programmed cell death.
Now, you might see a couple of different ways of describing the stages of cervical
intraepithelial neoplasia, but the most common is based on how much of the
epithelium is involved. 
Grade 1 cervical intraepithelial neoplasia affects the lower one-third of the
epithelium, thickness-wise. 
Grade 2 affects two-thirds, Grade 3 affects almost all of the epithelium, and
finally carcinoma in situ affects the entire thickness of the epithelium. 
The higher the grade, the more likely the dysplasia will evolve into cancer. 
Eventually, carcinoma in situ can progress to invasive cervical cancer, which is when
cancerous cells break through the epithelial basement membrane and into the
cervical stroma. 
Then, it can spread to neighboring tissues, like epithelial layers of the uterus and of
the vagina. 
Finally, it can pass through the pelvic wall and affect the bladder and rectum. 
Lastly, it can also spread via the lymphatic and circulatory systems to other areas of
the body like the liver and lungs. 
Because HPV tends to invade squamous cells first, the majority of cervical
cancer cases are squamous cell carcinomas. 
The second most common type, also associated with HPV, is
cervical adenocarcinoma, which involves the epithelial gland cells of the cervix. 
But either way, the progression from HPV infection to cervical intraepithelial
neoplasia to cancer is generally slow and it can take between 10 and 20 years
before invasive cervical cancer develops. 
Ok, now, since HPV is a sexually transmitted infection, the risk of developing cervical
canceris highest in females who do not use condoms and have multiple sexual
partners. 
Not every HPV infection results in cervical cancer, though. 
In fact, the immune system fights off most HPV infections. 
So it’s believed that there are other factors involved. 
For example, the risk increases depending on the type of HPV, how long the
infection lasts, and if the person is immunocompromised. 
Environmental factors like smoking also increase the risk.
But the good news is that vaccination against HPV immunizes against several HPV
types linked with cervical cancer, including HPV-16.
The first symptom of cervical cancer is often abnormal vaginal bleeding, especially
after sexual intercourse. 
Other symptoms include vaginal discomfort, vaginal discharge with an unpleasant
smell, and pain when urinating. 
If the cancer has spread beyond the pelvic wall, it can cause symptoms
like constipation and bloody urine.
Screening for cervical intraepithelial neoplasia and cervical cancer is done with
a Pap smearwith high-risk HPV testing. 
Pap tests are so good at detecting precancerous cells that screening recommends
a pap smear every 3 years for females between 21 and 65 years of age. 
Together with the HPV vaccine, this has contributed significantly to the drop in cases
of cervical cancer worldwide. 
Now, during a Pap test, some cells from the transformation zone are collected with a
brush and then they’re examined under a microscope for dysplasia. 
If the Pap test comes back positive for dysplasia, it may be followed up with
a colposcopy, which is when a magnifying device called a colposcope is used to get
a zoomed in view of the cervix, and then obtain biopsies. 
Treatment options for cervical intraepithelial neoplasia include cryosurgery, where
liquid nitrous oxide is used to freeze and kill abnormal cells, and conization, where
the transformation zone and some or all of the endocervix is removed surgically. 
Conization can be done with a scalpel, called cold-knife conization, laser, or
by heating a loop of thin wire with electricity, called loop
electrosurgical excision procedure or large loop excision of the transformation zone. 
Treatment of early cervical cancer is to surgically remove either just the tumor, or
also the uterus and associated lymph nodes.
If the cancer is more advanced, radiation and chemotherapy may be done.

Summary
All right, as a quick recap… Cervical cancer is a cancer of the female reproductive
systemaffecting the cervix. 
It’s most often a squamous cell carcinoma caused by a human
papillomavirus infection. 
It starts as cervical intraepithelial neoplasia and develops very slowly. 
Many cases of cervical cancer can now be prevented thanks to the HPV vaccine, or
caught very early on by screening for precancerous lesions with a Pap test. 
Precancerous lesions can be managed with cryosurgery or conization, whereas
treatment for cervical cancer is surgical.
Antimetabolit for cancer treatment
Antimetabolites are a diverse group of medications that are used for the treatment of
various conditions including cancer, infections and autoimmune disorders. 
In this video, we are focusing on the antimetabolites used in cancer treatment. 
Alright, during the S phase of the cell cycle, the cell performs DNA replication. 
DNA is composed of a sequence of deoxyribonucleotides and
each deoxyribonucleotide is made out of a phosphate group, a five carbon sugar like
deoxyribose, and a nucleobase, which can be either a pyrimidine like cytosine,
or thymidine, or a purine like adenine or guanine.
Now, nucleotide synthesis starts with ribose-5-phosphate, which is specific for RNA,
and an enzyme called ribose phosphate pyrophosphokinase uses an ATP to remove
two phosphate groups from it, attaching them to ribose-5-phosphate, creating
a phosphoribosyl pyrophosphate, or PRPP. 
Because it catalyzes the synthesis of PRPP, the enzyme ribose
phosphatepyrophosphokinase is also known as PRPP synthetase. 
Next step is to make pyrimidines. The amino acid glutamine, bicarbonate, and water
are used to form a molecule called carbamoyl phosphate which is then joined
to aspartate and together, they form a ringed molecule called carbamoyl aspartic
acid, which gets dehydrated to create a molecule called orotate. 
Next, an enzyme moves the phosphoribose unit from PRPP to orotate and that forms
orotidine monophosphate, or OMP. 
Next, the enzyme UMP synthase converts orotidine monophosphate
into uridinemonophosphate, or UMP. 
That UMP gets phosphorylated twice by nucleoside diphosphate kinase, to
become uridine triphosphate, or UTP. 
Finally, the enzyme CTP synthase, converts uridine triphosphate
into cytidinetriphosphate, or CTP. 
Now, purine synthesis starts with the amino acids glutamine, aspartate, and glycine,
together with bicarbonate and formate, which is the anion derived from formic acid. 
These undergo a ten-step pathway and the result is inosine monophosphate, or IMP,
which is sort of a generic purine. 
IMP can be converted to AMP and GMP. 
Okay, RNA nucleotides are usually in the monophosphate form, but to get
to DNAnucleotides, we need them in the diphosphate form, so CDP, UDP, ADP, and
GDP. 
Next, an enzyme called ribonucleotide diphosphate reductase will reduce
the ribose within them into deoxyribose, creating dCDP, dUDP dADP, and dGDP. 
After this, they just need to lose a phosphate group, and we'll have dCMP, dUMP,
dAMP, and dGMP. 
But, something is missing - dTMP. And here comes the folic acid, or vitamin B9,
which is converted to tetrahydrofolic acid, or THF.
THF acts as a mediator and accepts a “methylene” group from the amino
acid serine and transfers it to dUMP or deoxyuridine monophosphate. 
Then, an enzyme called thymidylate synthetase can convert dUMP to dTMP or
deoxythymidine monophosphate, and at that point we’re all set to make DNA.
Now, pyrimidine rings can be degraded completely back down to carbon
dioxide (CO2) and ammonia (NH3,) which can then be excreted from the lungs and
into urine.
In contrast, purine rings, or G and A are degraded down to
the metabolically inert uric acidwhich is then excreted into urine. 
For GMP to become uric acid, the enzyme purine nucleoside phosphorylase, first
removes the ribose and the phosphate from it, turning it into guanine. 
Next, another enzyme called guanase removes an amine
group turning guanine into xanthine. 
Finally, xanthine is oxidized into uric acid by the enzyme xanthine oxidase. 
On the other hand, for AMP to become uric acid, first the enzyme AMP deaminase
removes an amine group from it, turning it into IMP.
Then purine nucleoside phosphorylase comes in and removes the phosphate and
the ribose from IMP, making hypoxanthine. 
Hypoxanthine is then oxidised twice by xanthine oxidase - first to become xanthine,
and then finally, to uric acid. 
Now, it turns out that those intermediate molecules
in purine degradation, guanine and hypoxanthine, can be restored into fresh
new nucleic acids, through what is known as a salvage pathway. 
The enzyme hypoxanthine-guanine phosphoribosyl transferase, or HGPRT for short,
returns ribose and phosphate back to guanine to form GMP, and to hypoxanthine to
form IMP. 
Alright, now the cancer cells pretty much do nothing but divide all day long and so
they are very sensitive to cytotoxic medications that block DNA synthesis. 
The bad news is that plenty of normal cells in our body, like the cells lining the GI
tract, and the precursors to blood cells and platelets, are also actively dividing and
this explains why anticancer medications are toxic to these tissues. 
So the antimetabolites usually disrupt the pathway responsible for DNA synthesis by
mimicking nucleobases or folic acid, and cause DNA replication and cell proliferation
to come to a halt. 
Medications that mimic purine include azathioprine and cladribine, while medications
that mimic pyrimidine include cytarabine and 5-fluorouracil. Finally, there's folic
acid analogues like methotrexate.
Alright, let’s start with azathioprine which is the prodrug of 6-mercaptopurine, or 6-
MP. 
Azathioprine is converted to 6-MP by the enzyme thiopurine S-
methyltransferase and some 6-MP is converted to 6-thioguanine, or 6-TG. 
Both 6-MP and 6-TG act as purine analogs, and can conjugate with ribose and then
get phosphorylated to form nucleotides.
These nucleotides can mimic normal nucleotides and incorporate
into DNA halting DNA replication. 
Also, active metabolites of 6-MP inhibit two important enzymes in
the purine synthesis: PRPP synthetase and AMP deaminase. 
PRPP synthetase converts PRPP to IMP and AMP deaminase converts AMP to IMP
and so the end-result is the decreased production of IMP which, remember, is the
generic purine, and thus, nucleotide synthesis comes to a halt.
Notice also that allopurinol, which is an antigout medication, inhibits xanthine
oxidase, which is the enzyme that metabolizes 6-MP and
when azathioprine and allopurinol are used together, 6-MP increases to toxic levels. 
Moving on to indications. Azathioprine is used for the treatment of leukemias, such
as acute lymphoblastic leukemia, or ALL, and chronic myelogenous leukemia, or
CML. 
Now, an important side effect of azathioprine is bone marrow suppression which
leads to pancytopenia. 
When DNA synthesis is inhibited, megaloblastic anemia occurs. 
This and bone marrow suppression are common to all the antimetabolites used for
cancer treatment. 
The decrease in white blood cells leads to immunosuppression, increased risk for
infections and exacerbation of chronic infections such as hepatitis B infection
and herpes zoster virus infection. 
Other serious adverse effects include liver toxicity which manifests as cholestasis, or
decreased bile flow, and acute pancreatitis. 
Also, azathioprine is contraindicated during pregnancy due to its teratogenic effects. 
Acute toxic effects of azathioprine include gastrointestinal disturbances
like nausea and vomiting. 
Now, cladribine is another purine analog which can inhibit DNA proliferation through
various mechanisms. 
Cladribine gets phosphorylated to a triphosphate form which can be incorporated
into newly synthesized DNA strands. 
Cladribine can also inhibit DNA polymerase, the key enzyme of DNA replication. 
Either way DNA synthesis comes to a halt. Cladribine is also resistant to adenosine
deaminase which is the enzyme that normally degrades purines and so it can reach
very high levels inside the cells, decreasing the de novo purine synthesis. 
Moving on to indications, cladribine is the drug of choice for hairy cell leukemia and
can also be used for other types of leukemias. 
Side effects include bone marrow suppression and megaloblastic anemia. 
Alright, now let’s move on to pyrimidine analog. Cytarabine gets phosphorylated to
Ara-CTP, a triphosphate metabolite, that binds and competitively inhibits DNA
polymerase and thus, DNA synthesis. 
Cytarabine is indicated for hematologic
malignancies like leukemias and lymphomas. 
The main side effect of cytarabine is bone marrow suppression with megaloblastic
anemia, like the purine analogs. 
Now 5-fluorouracil, or 5-FU, is a pyrimidine analog that interferes with folic
acid cycle. 
5-fluorouracil gets metabolized to its active form which is 5-FdUMP and forms a
complex with THF. 
This complex can inhibit thymidylate synthase which normally binds to dUMP and
converts it to dTMP. 
Inhibition of thymidylate synthase results in decreased synthesis of thymidine which
is a DNA component. 
Other active metabolites of 5-fluorouracil can also be incorporated
into DNA and RNAresulting in inhibition of DNA and RNA synthesis. 
Now, unlike the other antimetabolites, 5-fluorouracil is indicated for solid tumors
rather than hematologic malignancies. 
Common indications include colorectal cancer and pancreatic cancer, but it’s also
indicated for head and neck cancer, breast cancer, ovarian cancer, bladder
cancer and hepatocellular cancer. 
What’s more, 5-fluorouracil can also be applied topically for the treatment of basal
cell carcinoma. 
Now, keep in mind that the effects of this medication can be enhanced with the
addition of leucovorin, which is also called folinic acid and it’s a reduced form of folic
acid. 
Moving on to the adverse effects. Like the rest of the antimetabolites, 5-
fluorouracil can cause bone marrow suppression and megaloblastic anemia. 
Other side effects include gastrointestinal disturbances like severe
diarrhea, mucositis, alopecia, CNS toxicity, cutaneous reactions such
as photosensitivity, and palmar-plantar erythrodysesthesia, or hand-foot syndrome. 
Now, in case of an overdose, uridine can be an effective antidote. 
Finally, an important antimetabolite is methotrexate which is a folic acid analog. 
Alright, DHFR normally converts DHF to THF which provide methyl groups
necessary for the synthesis of dTMP from dUMP and for purine synthesis. 
Now methotrexate has a higher affinity for DHFR, than DHF and so it binds
and irreversibly inhibits this enzyme. 
THF is also involved in synthesis of purines and amino acids as well. The result is a
decrease in synthesis of DNA, RNA, and proteins and thus, inhibition of cell division. 
Alright, methotrexate can be used for the treatment of leukemias, especially acute
lymphoblastic leukemia, or ALL, lymphomas such as primary CNS lymphoma and
non Hodgkin’s lymphoma, as well as solid tumors like breast cancer, head and neck
cancer, and bladder cancer.
Also, methotrexate can be used for conditions where there is abnormal proliferation
of trophoblastic tissue. 
It’s the drug of choice for early unruptured ectopic pregnancy, and choriocarcinoma,
which is a germ cell tumor. 
Apart from its use as an anticancer agent, methotrexate is also used for
inflammatory conditions like rheumatoid arthritis, psoriasis, inflammatory bowel
disease, systemic lupus erythematosus, and dermatomyositis. 
Now, let’s move on to side effects. Like all the antimetabolites, the major side effect
of methotrexate is bone marrow suppression and megaloblastic anemia. 
The good news is that myelosuppression can be reversed with folinic acid,
or leucovorin, and this strategy is called “leucovorin rescue”. 
Leucovorin is already a reduced form of folic acid and thus, it doesn’t
require dihydrofolate reductase to get activated. 
Also, leucovorin reverses the action of methotrexate by displacing it from its binding
sites. 
Another important side effect of methotrexate is liver toxicity which manifests as
macrovesicular fatty change, a severe form of hepatic steatosis where fat vesicles
displace the nucleus to the periphery of the hepatocyte, and pulmonary toxicity which
manifests as pulmonary fibrosis.
Also, use of methotrexate in pregnancy can lead to neural tube
defects and congenital heart defects.
So, methotrexate is contraindicated in pregnancy and characterized as category
X. Other side effects include alopecia, and mucositis. 
Now, let’s make a simple and fun mnemonic that’ll help you
efficiently memorize these pharmacology facts. We can set the scene in a port city.
The stormy ocean with its pouring rain is where we’ll put the purine analogues, the
city with its large pyramide will contain the pyrimidine analogues, and behind the city
there’s is a nice field for frolicing for the folic acid analogues. 
Now, in the stormy sea, we have a 19th century iron-clad battleship for cladribine.
On top of the ship, there’s a majestic zebra prince for azathioprine. Since both are
used to treat leukemia, a cancer of the blood and bone marrow, let’s paint a bone
with a crab eating the marrow on the side of the ship. 
Cladribine is the drug of choice for hairy cell leukemia so we can also have some
hair growing out of the gun turrets of the iron-clad. For side effects, we can put
some broken bones floating in the ocean for bone marrow suppression, and there’s a
bomb with a red blood cell drawn on it for megaloblastic anemia. 
Azathioprine causes liver damage and pancreatitis so we’ll have the Zebra prince
toss a damage liver inside a flaming frying pan into the sea. This drug is
also teratogenic so let’s have the Zebra’s pregnant wife scold him for polluting. 
Okay let’s head to the city for the pyrimidine analogues. First notice the largest
building in the city is Arabic styled for cytarabine. 5 flower girls are coming out of his
building to welcome the return of the prince and they represent 5-
fluorouracil. Cytarabine is used to treat leukemia so let’s put a big flag on the building
with the same “crab eating bone marrow” design as seen on the iron-clad. On the
flag pole, there’s a little bump that looks like a lymph node. There’s a little crab
hanging off of it since this drug can also treat lymphomas. 
5-fluorouracil is only used to treat solid tumors, so the 5 flower girls are dragging a
large, solid stone crab statue. The crab is wearing sunglasses and holding a bottle of
suntan lotion to help you remember basal cell carcinoma. Since the side effects of
both drugs include bone marrow suppression and megaloblastic anemia, let’s put the
bomb and the broken bones between the girls and the building. For the drug specific
side effects for 5-fluorouracil, let’s have one of the girls wearing sunglasses
for photosensitivity. The girl next to her is holding a toilet for severe diarrhea, The
next girl is holding a brain in a jar for neurotoxicity, and the 4th girl has large, swollen
hands and feet for hand-foot syndrome. The last girl’s got a big smile on her face
since she has the antidote, uridine. So she’s carrying a urinal with dinner plates in it. 
Finally, let’s head to the fields of frolicing for our folic acid analogues. Under a tree,
there’s a T-rex teaching math, for methoT-rexate. It’s standing on a stone crab statue
since it’s effective against solid tumors, and it’s holding a bone with a crab eating
the marrow for leukemias. A crab is pinching a lymph node on its neck
for lymphomas. On the tree, there’s a fruit that looks kind of like a fetus to help you
remember it’s used for ectopic pregnancies. On the same branch, there’s a bunch of
little crabs singing in a choire for choriocarcinoma. The dinosaur’s little claws are on
fire to help you remember it’s also used to treat inflammatory conditions
like rheumatoid arthritis. For side effects, let’s look at the students sitting around the
tree. One’s holding a broken bone and the bomb with the red blood cell, just like the
ones we saw in the other areas. The kid next to him also have a broken bone, but
luckily, he’s got a warranty, so he’s smiling. This is a reminder that leucovorin, or
lucky warranty, can reverse the bone marrow suppression caused by methotrexate.
The kid next to him is holding a damaged liver with a strip of bacon on top for hepatic
steatosis, and the last kid dozed off, so a spider is building a web on his chest
for pulmonary fibrosis. His pregnant mother is yelling at him to wake up and also to
help you remember this drug is teratogenic. 

Summary
All right, as a quick recap. The antimetabolites used for cancer treatment
include azathioprine and cladribine which are purine analogs, cytarabine and 5-
fluorouracil which are pyrimidine analogs, and methotrexate which is a folic
acid analog. 
They all inhibit DNA synthesis and so they act in the S-phase and are cell-
cycle specific. 
Azathioprine is used for the treatment of leukemias. 
Cladribine is the drug of choice for hairy cell leukemia. 
Cytarabine is indicated for hematologic malignancies like leukemias and lymphomas.
5-FU is indicated for solid tumors like colorectal cancer and pancreatic cancer, but
it’s also indicated for head and neck cancer, breast cancer, ovarian cancer, bladder
cancer and hepatocellular cancer. 
5-FU can also be applied topically for the treatment of basal cell carcinoma. 
Methotrexate can be used for leukemias, lymphomas, as well as solid tumors.
Also, it’s the drug of choice for early unruptured ectopic pregnancy, and for
the choriocarcinoma. 
The major side effect of all the antimetabolites used for cancer treatment is bone
marrow suppression but in the case of methotrexate, it can be reversed
with leucovorin.
Hematopoetic medication
Hematopoietic medications increase the amount of blood cells. 
Heme refers to blood and poiesis means to make. 
Specifically, hematopoietic medications increase the production of erythrocytes or
red blood cells, leukocytes or white blood cells, and platelets, which are
small clot forming fragments of a larger cell called a megakaryocyte.
Now, before we discuss these medications in detail, let's take a step back and talk
about the physiology of hematopoiesis, which can result in the production of over
one hundred billion new cells every single day! 
Hematopoiesis occurs in the bones of the body, but primarily in the bones of
the pelvis, ribs, and sternum.
This process starts in the bone marrow, the innermost portion of bone, where
the hematopoietic stem cells reside. 
These serve as progenitor cells for all the different cell types found in the blood. 
First, hematopoietic stem cells, also called hemocytoblasts, can
become lymphoidprogenitors or myeloid progenitors. 
The lymphoid progenitors can develop into lymphoblasts, which can then
differentiate into T-lymphocytes, B-lymphocytes, or natural killer cells. 
The myeloid progenitors can differentiate into erythrocytes, megakaryocytes,
or myeloblasts, which can then become immune
cells like monocytes, neutrophils, basophils, and eosinophils. 
Now, in order for a hematopoietic stem cell to reach its final, mature form, the cell
needs to receive the appropriate signals in the form of specific growth chemicals,
called growth factors or stimulating factors. 
While there are a multitude of these factors that cause differentiation of these cells,
we're only going to discuss the most important ones related to hematopoietic
medications.
First, GM-CSF, or granulocyte macrophage colony stimulating factor, and G-CSF,
or granulocyte colony stimulating factor, are glycoproteins released in response to
infection by the endothelium, which is the inner lining of blood vessels, and immune
cells such as macrophages, T-cells, and natural killer cells.
GM-CSF stimulates myeloid progenitors and cause them to divide and differentiate
into all of its derivative cell types. 
It also speeds up the maturation
of monocytes (or macrophages), neutrophils, eosinophils, and basophils so they’ll be
ready for action. 
G-CSF, on the other hand, specifically induces myeloblasts to mature
into neutrophils. 
Next, thrombopoietin is a glycoprotein produced in the liver and kidneys. 
It stimulates hematopoietic stem cells to differentiate into megakaryocytes, and also
speeds up their maturation and fragmentation to generate platelets. 
IL-11, or interleukin eleven, is a glycoprotein released by bone marrow cells that
work in conjunction with thrombopoietin to stimulate megakaryocyte maturation
and plateletproduction. 
Finally, erythropoietin or EPO, which is produced in the kidneys, and to a lesser
extent in the liver, stimulates hematopoietic stem cells and myeloid progenitors to
differentiate into erythrocytes, or red blood cells. 
Now, most hematopoietic medications act like analogues or synthetic versions of
these growth factors. 
Let’s start with sargramostim which is a synthetic version of GM-CSF. 
Sargramostim is often used to boost myeloid precursor production and maturation
after a person undergoes a bone marrow transplant.
Other uses for sargramostim include increasing the myelocyte derived white blood
cellcount following chemotherapy or radiation therapy. 
These therapies target rapidly dividing cells like cancer cells, but hematopoietic stem
cellsin the bone marrow are also dividing rapidly, so they almost always get affected
too. This is called bone marrow suppression. 
In some people, sargramostim can cause life threatening allergic reactions,
called anaphylaxis, where blood vessels dilate, leading to hypotension. 
It can also cause a problem known as capillary leak syndrome, where fluids leak
from the capillaries into the surrounding tissue, causing severe edema, or swelling.
Other problems associated with this medication include fever and arthralgias, or joint
pain.
The medication filgrastim is a recombinant G-CSF and is used to
correct neutropenia, or low neutrophil count. 
So it’s used in diseases that decrease neutrophil production
like leukemia, myelofibrosis, and chronic idiopathic neutropenia. 
Another indication is for people undergoing treatments that
inhibit neutrophil production, like chemotherapy or radiation therapy. 
Unlike sargramostim, the toxicity associated with filgrastim is minimal. 
The most commonly reported side effect is bone pain, which results from the high
production of new neutrophils in the bone marrow. 
Severe allergic reactions can also occur, but are very rare. 
Now, romiplostim, eltrombopag, and oprelvekin are all medications that
stimulate plateletproduction to treat thrombocytopenia, or low platelet count. 
Romiplostim is recombinant thrombopoietin, where as eltrombopag is a synthetic
drugthat acts as an agonist at the thrombopoietin receptor on myeloid progenitor
cells to stimulate megakaryocyte production. 
Both romiplostim and eltrombopag are used to treat disorders where the body starts
breaking down platelets, like idiopathic thrombocytopenic purpura. 
These medications can exhibit serious side effects including increased risk of clot
formation due to an increase in platelet production, and eltrombopag has been
associated with liver toxicity and severe bleeding, limiting its use. 
The medication oprelvekin is a recombinant form of IL-11, which also
stimulates plateletproduction following chemotherapy. 
Oprelvekin’s toxicities include edema, palpitations, nausea, and vomiting. 
Lastly, the medication epoetin is a recombinant erythropoietin, or EPO, which
stimulates the production of new red blood cells. 
Epoetin is an incredibly powerful drug for the treatment of anemia, or low red blood
cell count, especially when the anemia is due to chronic renal failure where the
damaged kidneys can’t produce enough EPO. 
It’s also useful for correcting anemias caused by other medications like
the HIV drug zidovudine, as well as anemia caused by certain cancers like leukemia,
and anemia in critically ill patients, called anemia of chronic disease. 
It’s important to note that several weeks of therapy are required before erythrocyte
counts rise, so it is not an alternative to transfusing blood. 
In general, epoetin is a well tolerated medication, but it could
cause hypertension and increase clot formation since there’s more red blood cells in
the blood.

Summary
All right, as a quick recap, hematopoietic medications help to generate different
types of blood cells including white blood cells, megakaryocytes, and red blood
cells. 
They work by acting as analogues of the various physiological growth
factors produced by the body. 
They are used in disorders that decrease the levels of specific blood cells
or platelets, but they are also used after treatments like chemotherapy or radiation
therapy that suppresses the bone marrow.
Dna alkylating medication
DNA alkylating medications are a class of drugs that's mainly used as anticancer
agents. 
They disrupt the structure of DNA by adding an alkyl group to the guanine base and
can affect all phases of the cell cycle.
Alright, the cell cycle refers to the events that somatic cells, which includes all of the
cells in our bodies except the reproductive cells, go through from the moment they’re
formed until the moment they divide into two identical daughter cells.
This cycle varies in length depending on the type of cell. For rapidly dividing cells,
like skin cells, it takes less than a day, whereas for other cells, like liver cells, the cell
cycle can last years. 
Now, the cell cycle can be divided in two phases: interphase and mitosis. 
Interphase comprises of the G1 phase, during which the cell grows and performs its
cell functions, the S phase, during which DNA is replicated, and the G2 phase,
during which the cell grows again before entering mitosis. 
Mitosis can be broken down into prophase, metaphase, anaphase, and telophase,
during which the replicated DNA divides equally for the two daughter cells, and ends
with cytokinesis, which is when the cell membrane actually divides to form the two
new cells. 
There’s also a G0 phase which is an extended G1 phase where the cell is resting
and not actively preparing to divide. 
Alright, now imagine a cancer cell. This cell is going through the phases of the cell
cyclewithout regulation, and its DNA also replicates more frequently and with less
error-correcting than healthy cells. Therefore, it’s more sensitive to DNA damage.
Here’s a DNA base, guanine. Alkylating agents attach an alkyl group at the number 7
nitrogen atom of guanine.
Now, repair enzymes recognize there’s something wrong, so they attempt to replace
the alkylated bases and cause fragmentation of the DNA, or DNA strand breakage. 
When this section of the DNA is repaired, abnormal base pairing could result, like
having a thymine paired up with guanine instead of the usual cytosine. Eventually
the DNA damageresults in cell death. 
Now, another mechanism by which alkylating agents cause DNA damage is
the crosslinking of DNA. 
In this process, an alkylating agent that has two DNA binding sites causes
two guaninebases to link together, forming a covalent bond, leading to the formation
of cross-bridges.
Cross-linking prevents DNA from being separated for replication or transcription,
eventually resulting in cell death. 
DNA alkylating medications are cell cycle-nonspecific agents, meaning they act on
tumor cells during all phases of the cell cycle, including the resting G0 phase.
Okay, let’s start with the nitrogen mustards, which
include cyclophosphamide, mechlorethamine, and ifosfamide. 
Nitrogen mustards are related to phosgene, the lethal ‘mustard gas’ that was used
during World War I, but it’s also the first intravenous chemotherapy treatment for
cancer. 
Alright, now these agents are prodrugs, meaning that they are administered in an
inactive form which needs to be metabolized into an active form by the
liver cytochrome P450 enzymes. 
Now moving onto the indications, cyclophosphamide and ifosfamide can be used in
various types of cancers. 
They are used against leukemias, which are a type of cancer that affect the cell in
the bone marrow that eventually becomes white and red blood cells,
and lymphomas, which are cancers of the immune cells in the lymph nodes. 
It can also treat other solid tumor cancers like ovarian and breast cancer. 
Apart from the treatment of cancer, high doses
of cyclophosphamide is immuno ablativeand can be used to treat small-
vessel vasculitis like granulomatosis with polyangiitis and microscopic polyangiitis,
and also in polyangiitis nodosa, which is a medium-vessel vasculitis. 
Finally, cyclophosphamide can be used for progressive or refractory cases
of systemic lupus erythematosus, an autoimmune disease affecting multiple organs,
and for multiple sclerosis, a demyelinating disease of the central nervous system. 
In terms of toxicity, all alkylating agents depress bone marrow function and can
cause aplastic anemia. 
However, the most dangerous thing is the risk of developing leukemia or other
malignancies after prolonged use. 
Other common toxicities with these medications include hair loss, gastrointestinal
disturbances, and depression of gametogenesis, which can cause infertility. 
Finally, alkylating medications are teratogens, meaning that they disrupt fetal
developmentand can lead to birth defects. 
Now, nitrogen mustards specifically, can cause syndrome of inappropriate
antidiuretic hormone secretion, which can be shortened to SIADH. 
This is where an inappropriate presence of antidiuretic hormone causes water
retentionand euvolemic hyponatremia. 
Cyclophosphamide can also cause bladder cancer and hemorrhagic cystitis, which is
very common, however there’s also good news. 
Hemorrhagic cystitis can be prevented by increasing fluid intake and administering
compounds that are sulfhydryl donors, like mesna or sodium-2-mercaptoethane
sulfonate. 
Alright, let’s move on to busulfan. Unlike cyclophosphamide, busulfan does not
require any bioactivation in order to fight tumor cells. 
It’s highly toxic to the bone marrow, but not the other organs. 
Therefore, it’s one of the most potent agents against leukemia, and is especially
effective against chronic myelogenous leukemia, or CML, a type of blood cancer that
affects granulocytes. 
It decreases the formation of granulocytes and platelets at low dosage, and red cells
in higher dosage. 
Now busulfan is used before bone marrow transplant as a part of myeloablative
conditioning, where both the cancer cells and healthy bone marrow are destroyed to
make room for the new bone marrow. 
Now the side effect is of course, the suppression of the bone marrow, leading to
decreased platelets, red blood cells, and white blood cells. 
Other less frequent toxicities include: pulmonary fibrosis, where
excess collagen or scar tissue form in the interstitial tissue of the lung;
and hyperpigmentation, or darkening of the skin.
Okay, now nitrosoureas, which include carmustine and lomustine, also require
activation in the liver by the cytochrome P450. 
They are highly lipid-soluble medications, meaning they can cross the blood-brain
barrierand that’s why they are primarily used to treat brain tumors, like glioblastoma
multiforme. 
However, when they are also neurotoxic and can cause convulsions, seizures,
and ataxia, or poor coordination of muscle movements. 
Now, let’s make a simple and fun mnemonic that’ll help you
efficiently memorize these pharmacology facts about DNA alkylating medications. So
first, let’s imagine we are in a store that sells alkaline batteries. 
The first customer is a cyclops for cyclophosphamide. He’s wearing a mechanic’s
outfit to represent mechlorethamine. He wants to buy batteries for his knock-off I-
fone, to represent ifosfamide. He lets loose a mighty fart cloud that’s mustard-yellow
in color, to help you remember these are nitrogen mustards. For indications, let’s use
crabs to represent cancer, since in the zodiac, cancer is a giant crab. So
for leukemia, let’s have the cyclops holding a bone club in one hand, with little crabs
in the marrow. Next, he’s got a large lymph node on his neck with a crab pinching it
for lymphomas. A crab is also in his chest pocket pinching inappropriately to help
you remember the solid tumors like breast cancer. For the non-cancer indications,
let’s use the cyclop’s pet wolf, which represents lupus. On its back, are multiple
scarecrows for multiple sclerosis. The wolf has bulging arteries on its body to
represent the different vasculitides that cyclophosphamide can also treat. For side
effects, the cyclops is wearing a diaper for the syndrome of inappropriate antidiuretic
hormone. There’s a big bloody spot on it, to help you remember hemorrhagic
cystitis. 
Next, let’s move on to busulfan, which is a businessman who’s also a sultan.
He’s riding a camel that’s just a skeleton to help you remember it’s very toxic to
the bone marrow. The camel represents CML, but it’s also effective against
other leukemias. Finally, the fact that it’s all bones will help you
remember busulfan is used before bone marrow transplants. For side effects,
a spider built a web on the camel’s chest to represent pulmonary fibrosis, and the
skull is scorched black for hyperpigmentation. 
Okay, the last group of medications are the nitrosoureas
like carmustine and lomustine. So let’s have a nitro powered Mustang-
limo crash through the store. The VIP is a crab with a giant brain, since their main
indication is brain cancers. These drugs can cause CNS toxicity like seizures, which
is why the driver crashed. Okay, so let’s use the couple who owns the store to
represent the side effects common to all the DNA alkylating agents. One of them is
a balding man, which represents hair loss. The man is saying he wants a vasectomy
to help you remember infertility. His wife is pregnant, to help you remember these
medications are teratogenic, and she’s so angry she snapped a bone in half, to
represent bone marrow suppression. Finally, the arguing couple is surrounded by
crabs, since all the alkylating agents increase the risk of developing malignancies. 

Summary
All right, as a quick recap…DNA alkylating agents are a class of medications used
primarily in the treatment of cancer. 
They are cell cycle-nonspecific agents, meaning they target all phases of the cell
cycle. 
Cyclophosphamide and other nitrogen mustards can treat leukemias, lymphomas,
and solid tumor malignancies.
Busulfan targets bones and is primarily used for leukemias and myeloablative
conditioning before bone marrow transplant. 
Nitrosoureas, cross the blood-brain barrier and are mainly used in brain cancers. 
Side effects of all alkylating agents include myelosuppression, hair loss,
gastrointestinal disturbances, and after prolonged use, sterility and high risk for
developing leukemia or other malignancies.
Monoclonal antibodies
With monoclonal antibodies, antibodies means that they target a specific antigen
with an antibody-antigen binding; and monoclonal means that each antibody is
produced from a specific B cell line.
Okay, now monoclonal antibodies are used for the treatment of cancer and various
autoimmune diseases like multiple sclerosis and rheumatoid arthritis. 
In this video, we are focusing on the monoclonal antibodies that are used for cancer. 
Normally, all of our cells grow and divide through a tightly regulated cell cycle once
they receive growth factor signals. 
During the cell cycle, if a cell appears abnormal in any way to the immune cells that
do constant surveillance, the cell has to fix the problem or undergo apoptosis,
or programmed cell death - a bit like cellular suicide, rather than proceed to the next
phase of the cell cycle. 
But cells can become mutated due to environmental or genetic factors. 
A mutated cell becomes cancerous when it starts to divide uncontrollably. 
As cancer cells start piling up on each other, they form a small tumor mass and they
need to induce blood vessel growth, called angiogenesis, to supply themselves with
enough energy. 
Some tumors produce vascular endothelial growth factor, or VEGF, which binds to
VEGF receptors found on vascular endothelial cells and stimulates angiogenesis. 
Also, many tumors overexpress growth factor receptors like the epidermal growth
factor receptor, or EGFR, and the human epidermal receptor 2, or HER2, that
stimulate cell proliferation and tumor growth. 
Malignant tumors are ones that are able to break through the basement membrane.
Some of these malignant tumors go a step further and detach from their basement
membrane at the primary tumor site, enter nearby blood vessels or the lymphatic
system, and establish secondary sites of tumor growth throughout the body—a
process called metastasis. 
Now, the monoclonal antibodies that are used for the treatment of cancer target
specific antigens that are usually overexpressed in cancer cells. 
Once these antibodies bind to the cancer cells, they can trigger apoptosis, promote
the formation of MAC complexes which trigger complement-mediated cell lysis, or
attract other immune cells to attack the cancer cells. 
Furthermore, a lot of these antigens are actually the cell receptors that promote
growth and proliferation. 
So when the monoclonal antibodies bind, they prevent these receptors from
functioning. 
These medications are all administered intravenously because they're all proteins,
which means they’ll be destroyed in the GI tract if taken perorally.
Common monoclonal antibodies
include bevacizumab, cetuximab, rituximab, trastuzumab, and alemtuzumab; they all
have the suffix “-mab,” which is characteristic of antibodies. 
Okay, let’s start with cetuximab. Cetuximab binds EGFR, or epidermal growth
factorreceptors, that has tyrosine kinase activity. 
Once activated, this receptor phosphorylates various target proteins in signaling
pathways. 
One of these is a protein called K-ras, which activates cell proliferation, migration,
and angiogenesis. 
Now, many cancer cells overexpress EGFRs or have mutated EGFRs that are more
active than normal, so cetuximab can block these receptors and prevent the cancer
cells from proliferating and metastasizing. 
However, in certain cases there could be a mutation in the K-ras gene, causing the
protein that’s produced to always be turned on. 
In these cases, they’re not regulated by EGFR, so cetuximab will have no effect. 
Common uses for cetuximab include the treatment of the metastatic stage
of colorectal cancer and for the treatment of head and neck cancers. 
Alright, let’s move on to side effects. Cetuximab is a chimeric antibody, which means
that it has both human and non-human components and thus the immune
system recognizes it as foreign, leading to various hypersensitivity reactions like skin
rashes, pruritus, headache, fever, and mild hypotension. 
Now, other side effects include gastrointestinal symptoms like diarrhea, elevation
of liver enzymes, and skin toxicity like acneiform skin rashes, dryness, and pruritus. 
Okay, next up is trastuzumab, also known as herceptin. Trastuzumab targets
human epidermal growth factor receptor 2, or HER2, which also has tyrosine
kinase activity.
Since HER2 activation stimulates signaling pathways that lead to cellular
proliferation, a mutation or overexpression of this receptor can lead to cancer. 
Now trastuzumab is most commonly used to treat breast cancer that’s HER2
positive, meaning the cancer cells overexpress the HER2 protein. 
It’s also used in gastric, ovarian, and lung cancers that are caused by HER2
mutations, but they are more rare than breast cancer. 
Now the main side effect of trastuzumab is cardiotoxicity, since cardiomyocytes also
have a lot of HER2, and trastuzumab can damage these cells, leading to heart
failure. 
Other side effects include gastrointestinal symptoms like nausea, diarrhea,
fever, chills, and headache. 
Next up is bevacizumab, which binds to VEGF, or vascular endothelial growth
factors. 
Cancer cells have these growth factors on their surface which causes nearby blood
vessels to grow offshoots towards the tumor to supply it. When VEGF is blocked, it
causes the cancer to become deprived of its blood supply and dies off. 
Bevacizumab is used for the treatment of solid tumors like colorectal cancer, renal
cell carcinoma, breast cancer, and non-small cell lung cancer, especially in
metastatic stages. 
Another use for bevacizumab is for the treatment of age related macular
degeneration, which is caused by the growth of abnormal, leaky blood vessels that
cause damage to the retina. 
Moving on to side effects, bevacizumab can cause inhibition of angiogenesis in
normal tissues and leads to impaired wound healing. 
It can also cause hemorrhages, which can present
as epistaxis or nosebleed; hemoptysis, or coughing up of blood; gastrointestinal
bleeding; and intracerebral hemorrhage. 
Other side effects include perforation of the GI tract and increased thrombosis,
leading to strokes and myocardial infarctions.
Okay, let’s move on to rituximab. Rituximab binds to CD20, an antigen found on B
cellmembranes and leads to cell death through multiple mechanisms. 
First it activates the complement system initiating the formation of the membrane
attack complex that creates holes on the cell membrane, ultimately leading to cell
lysis. Also, rituximab induces apoptosis, or programmed cell death. 
In addition, rituximab activates antibody-dependent cell-mediated cytotoxicity, where
the bound antigen-antibody complex gets recognized by immune cells called natural
killer cells, which form pores in the cell that allow the entry of enzymes that work like
silent assassins to cause cell death. 
Moving on to indications. The CD20 antigen is found on both normal and
malignant B cells, so rituximab is used primarily for the treatment of non-Hodgkin B
cell lymphomas. 
It’s also indicated for chronic lymphocytic leukemia, or CLL, where there is abnormal
proliferation of B cells and T cells. 
Aside from cancer, it’s also useful for treating autoimmune diseases where there is
abnormal activation of the immune cells like in rheumatoid arthritis.
Rituximab is also used for the treatment of idiopathic thrombocytopenic purpura, or
ITP, where B cells produce antibodies that destroy platelets. 
The bad news is that rituximab can cause hypersensitivity reactions because it’s
a chimeric antibody like cetuximab. 
Other side effects include suppression of the immune system and reactivation of
viruses such as JC virus, or John Cunningham virus. 
This particular virus causes a demyelinating disease of the central nervous
system called progressive multifocal leukoencephalopathy, or PML and is potentially
life threatening. 
Finally, alemtuzumab is a humanised monoclonal antibody that’s similar
to rituximab since it also binds targets immune cells. 
However, instead of binding to CD20, it binds to CD52, which is found on the
membrane of all lymphocytes including B cells, T cells, and natural killer cells, as
well as monocytesand dendritic cells.
Alemtuzumab binds to both the normal and malignant versions of these cells and
designate them for destruction by natural killer cells, complement-mediated lysis, or
just apoptosis. 
It’s main indications include chronic lymphoid leukemia, or CLL, and immune-
mediated disorders like multiple sclerosis. 
Since we are killing the lymphocytes and monocytes, the main adverse effects
are immunosuppression and an increased risk of infections. 
Now, let’s make a simple and fun mnemonic that’ll help you
efficiently memorize these pharmacology facts about monoclonal antibodies. So
for monoclonal antibodies, let’s use a colony of ants. 
For cetuximab, let’s have an ant wearing a tuxedo covered in cement. He’s bringing
a plate of Fried Eggs back to the colony, which represents its target antigen, EGFR.
For indications, let’s use crabs to represent cancer, since in the zodiac, cancer is a
giant crab. For cetuximab, there’s a crab pinching the ant’s neck for head and neck
cancers, and there’s one pinching his butt for colorectal cancer. For side effects,
unfortunately the ant was allergic to eggs so he developed a hypersensitivity
reaction and is covered in rashes. 
Next up is rituximab, so here we have an ant wearing a ripped tuxedo. He’s selling
his music CDs for 20 cents each, which represents CD20. For indications, we’ve
used a hedgehog for hodgkin's lymphoma, but since rituximab is used for non-
hodgkin’s lymphoma, we’ll have a hedgehog without spines. Now, he’s trying to buy
the CDs but these CDs are clearly pirated, so let’s put the poor guy in a prison CeLL
for CLL, and there’s a little Teepee inside for ITP. In terms of side effects, this ant
also have a rash to represent a hypersensitivity reaction. He’s wearing a dead white
blood cell like a hat to help you remember immune suppression, and there are large
white spots on his head for progressive multifocal leukoencephalopathy. 
The next ant is eating a giant almond for alemtuzumab. He’s also selling his pirated
CDs but they are 52 cents each which represents CD52. Three scarecrows
representing multiple sclerosis are trying to buy the CDs and they are also arrested
and put into a Cell for CLL. For side effects, let’s put a dead white blood cell on the
ant’s head for immune suppression, but he doesn’t have any rashes because
the alemtuzumab is a humanized antibody, so it’s less likely to cause
a hypersensitivity reaction. 
Okay, the next drug is bevacizumab, which will be represented by an ant wearing a
beaver mask and a fake tail. This ant is carrying a basket full of vegetables for
VEGF, and he’s sitting on a large stone crab statue to help you remember it’s used
for tumors that are solid, rock solid! For noncancerous indications, we’ll give the ant
an old fashioned monocle, to help you remember it’s also used to treat age-related
macular degeneration. For side effects, let’s cover his vegetables in blood clots to
help you remember it increases the risk of thrombosis. He was wounded while
foraging for food and there’s a big hole in his abdomen through which you can see
the intestines. This will help you remember bevacizumab-impaired wound
healing and GI perforation. Lastly, there’s a pool of blood under him to represent
hemorrhaging. 
Okay, for the final drug, let’s have a lady ant carrying a trash can since she
represents trastuzumab. She brought along HER 2 daughters since this drug
targets HER2. The 2 of them are holding a giant bra with a crab hanging off of it to
help you remember it’s mainly used to treat HER2 positive breast cancer. For side
effects, there’s a large shattered heart in the trash can, to represent heart failure. 

Summary
All right, as a quick recap… Monoclonal antibodies that are used for the treatment of
cancer, include bevacizumab, cetuximab, rituximab, trastuzumab,
and alemtuzumab. 
Bevacizumab targets VEGF and is used for the treatment of solid tumors. 
Cetuximab targets EGFR and is used primarily for colorectal cancer or cancers of
the head and neck. 
Rituximab binds to CD20 found on B cell membranes and is used primarily for the
treatment of non-Hodgkin’s lymphomas, but also for CLL, rheumatoid arthritis, and
ITP. 
Trastuzumab, also known as herceptin, binds to HER2 and is used primarily
in breast cancers that overexpress HER2. 
Alemtuzumab binds to CD52 found on lymphocytes and monocytes and is used for
CLL and multiple sclerosis.
Anti tumor antibiotics
Alright, we know that antibiotics kill microbes, but a certain class of antibiotics called
antitumor antibiotics can kill cancer too. 
Antitumor antibiotics include products that are produced from Streptomyces bacteria
like: bleomycin; anthracyclines like doxorubicin and daunorubicin; and dactinomycin,
also called actinomycin D.
These medications interfere with DNA replication and often damage the DNA itself,
leading to cell death. Most of them are cell cycle non-specific. 
Now, the cell cycle refers to the events that somatic cells go through in order to
divide into two identical daughter cells. 
The cell cycle can be divided in two phases: interphase and mitosis. 
Interphase starts with the G1 phase during which the cell grows and performs its cell
functions. 
At the end of G1, there's a control point called the G1 checkpoint - where the cell
checks to see if the DNA is damaged and it synthesized the right proteins in the
correct amount.
If there is any reason for the cell not to divide, the cell can either enter a non-dividing
state, called the G0 phase, where the DNA repair mechanisms try to fix the problem,
or the cell can self-destruct in a process called apoptosis. 
Now, if the cell does get the go-ahead at the G1 checkpoint, it enters the S
phase during which DNA is replicated. 
Okay, so during DNA replication, we unzip the double helix with the enzyme DNA
helicase, and this creates a replication fork, with the two prongs of the fork being the
two strands that are separated from one another. 
Now, as DNA helicase does its thing, the segments of DNA ahead of it start to
overwind, meaning, the double helix becomes more tightly wound. 
Overwinding of the DNA can slow down replication, so the enzyme DNA
topoisomeraseworks ahead of DNA helicase to loosen up the tight DNA coils. 
Next, RNA primase creates a matching RNA primer on one prong of the
the replication fork. 
This is the area where the next enzyme, DNA polymerase can bind to the DNA to
use it as a template and start adding nucleotides that’re complementary to
the DNA onto the end of the primer. Eventually we get a completed complementary
copy of the DNA. 
Next is the G2 phase, during which the cell grows again before entering mitosis. 
However, before it can do that, it must pass the final G2 checkpoint to make sure
there is no DNA damage after replication.
Now, during mitosis, the replicated DNA divides equally for the two daughter cells,
and the cell cycle ends with cytokinesis, which is when the cell membrane actually
divides to form the two new cells. 
Alright, now the cancer cells are also going through the phases of the cell cycle, but
they undergo this process much more frequently and without checking for errors. 
Therefore, cancer cells are more sensitive to DNA
damage from cytotoxic medications like the antitumor antibiotics. 
There are also normal tissues that divide rapidly like bone marrow and hair follicles,
and they are also more susceptible to damage, which explains
why cytotoxic medications are more toxic to these tissues. 
Okay let’s start with bleomycin, which is a peptide that has an iron binding site on
one end and a DNA binding site on the other end. 
Bleomycin binds to the DNA strand and in the presence of oxygen, it becomes
activated and acts as an oxidase, which means it transfers electrons from the iron to
the oxygen molecule, generating free oxygen radicals. 
These oxygen radicals oxidize DNA bases, causing breaks in the DNA strand. 
Note that bleomycin is a cell cycle specific medication that is mostly effective in
the G2 phase. 
Bleomycin plays an important role in the treatment of
Hodgkin’s lymphoma and testicular cancer but it’s also used to treat squamous cell
carcinoma of the skin.
Now, bleomycin is inactivated by an enzyme in our body called hydrolase, but
tissues like lungs and skin have lower levels of this enzyme, so bleomycin becomes
toxic. 
As a result, a super important side effect of bleomycin is pulmonary toxicity, which
usually presents as pneumonitis, but can turn into life-threatening pulmonary
fibrosis. 
Skin toxicity presents with rash, exfoliation, and hyperpigmentation or darkening of
the skin. 
Bleomycin is also associated with mucous membrane toxicity, which manifests
as stomatitis and mucositis in the mouth, and alopecia or loss of hair. 
What is special with bleomycin is that it only causes minimal myelosuppression,
which is unusual for an anticancer medication. 
Now, let’s move on to dactinomycin or actinomycin D. Dactinomycin is a peptide
that intercalates into the DNA molecule, which means that it inserts itself between
the normal base pairs. 
As a result, RNA and DNA polymerase can’t bind to DNA, so RNA and DNA
synthesiscome to a halt. 
In addition, dactinomycin can also generate free radicals like bleomycin, and cause
breaks in the DNA strand. 
Note that dactinomycin is cell cycle non-specific, meaning they act on tumor cells
during all phases of the cell cycle, including the resting G0 phase. 
Dactinomycin is used primarily in the treatment of pediatric tumors
like: nephroblastomaor Wilms tumor; rhabdomyosarcoma, which is a type of cancer
that develops from skeletal muscle cells; and Ewing sarcoma, which is a
malignant bone tumor. 
Also, dactinomycin is associated with significant myelosuppression and alopecia. 
Alright, moving on to anthracyclines which include doxorubicin, daunorubicin,
idarubicin, and epirubicin. 
Anthracyclines are cell-cycle non specific medications and act through various
mechanisms. 
First, they intercalate with DNA like bleomycin, inserting themselves between base
pairsand inhibiting RNA and DNA synthesis. 
Anthracyclines also inhibit topoisomerase II and thus DNA will overwind during
replication until it tears itself apart. 
In addition, anthracyclines also produce free oxygen radicals that damage the DNA
strand, but they need to bind to iron found in the tissue to do so. 
Indications for anthracyclines include the treatment of solid tumors like
breast, thyroid, lung, and ovarian cancers, but also leukemias and lymphomas. 
Now an important side effect of these medications is cardiotoxicity due to the buildup
of free radicals in the myocardium. 
Cardiotoxicity manifests as dilated cardiomyopathy that is dose dependent and
irreversible when it happens. 
But the good news is that cardiotoxicity can be prevented with dexrazoxane, which is
an iron chelating agent that binds to iron in the myocardium and prevents the
production of free oxygen radicals. 
Other side effects include myelosuppression and alopecia. 
Now, let’s make a simple and fun mnemonic that’ll help you
efficiently memorize these pharmacology facts about antitumor antibiotics. Okay,
let’s imagine we’re in a playground with a crisscrossing slide that looks like
a DNA helix. 
Standing on the top of the slide, we have the anthracyclines
like doxorubicin and daunorubicin. They will be represented by a little girl wearing a
giant ruby necklace since they all end in “rubicine.”
Now, she’s holding a balloon with O2 written on it because anthracyclines
generate free oxygen radicals. Next, she’s got a large topaz ring
for topoisomerase inhibition. And finally, she’s standing on the DNA slide because
these drugs also intercalate DNA. 
Okay, going down the slide, we have an actor mouse who’s dressed like
Shakespeare, but he’s got a large “D” on his clothing for dactinomycin,
or actinomycin D. He’s also holding a balloon with O2 on it because this drug also
generates free oxygen radicals. Since he’s also on the slide, he’s a DNA intercalator
too! 
Finally at the bottom of the slide, we have bleomycin, which is represented by a
bleeding mouse who got injured on the slide. Like the other two, he’s holding the free
oxygenradical balloon, but since he’s off of the slide, he does not intercalate DNA. 
Okay, now that the mechanisms are out of the way, let’s go over indications and side
effects. For indications, let’s use crabs to represent cancer, since in the zodiac,
cancer is a giant crab. So on the top of the slide by the anthracyclines, there’s a crab
statue made of solid stone, since these medications treat solid tumors. Let’s put a
little bowtie that looks like a thyroid on the statue since these medications are good
against thyroid cancer. Next, the statue is holding a giant bone club with little crabs
in the marrow, which represents leukemia. Finally, a crab is pinching a lymph node
on the girl’s neck for lymphoma. For side effects, let’s give the rubicine kid a heart-
shaped balloon. This balloon is too full, and looks like it’s about to pop, which
represents dilated cardiomyopathy. Tied to the string of the balloon is a broken bone
for bone marrow suppression.
Okay moving on, next we have dacinomycine in the middle of the
slide. Riding behind the shakespeare mouse, there’s a baby crab to help you
remember this drug treats pediatriccancers. The baby crab is fighting an earwig to
help you remember one of these pediatriccancers is Ewing’s sarcoma. For side
effects, let’s have them fighting over a broken bone for bone marrow suppression.
Okay, moving on. 
At the bottom of the slide we have bleomycin. This mouse’s pet hedgehog, for
Hodgkin’s lymphoma, is checking to see if the bleeding mouse is okay, and it’s
wearing a jockstrap for testicular cancer. A little crab is pinching a tumor on the
injured mouse’s face, which represents skin cancers like squamous cell carcinoma.
For side effects, a paramedic is at the scene to check up on the injured individuals.
He put a spiderweb on the mouse’s chest wound, which represents pulmonary
fibrosis. He’s been working outside too long and his face is very tan, which
represents skin hyperpigmentation. Finally, he’s wearing red lipstick on his big lips,
which represents mucositis and stomatitis.
13.svg All right, as a quick recap. Antitumor antibiotics are a class of medications
that are produced by Streptomyces bacteria and are used in the treatment of
cancer. 
They include bleomycin, dactinomycin, and anthracyclines
like doxorubicin, daunorubicin, idarubicin, and epirubicin. 
They interfere with the cell-cycle through various mechanisms. 
They are all cell-cycle non-specific, except bleomycin which is cell-cycle specific and
acts in the G2 phase. 
Bleomycin is used for the treatment of Hodgkin’s lymphoma and testicular
cancer and can cause pulmonary toxicity, but only minimal myelosuppression.
Dactinomycin is used for the treatment of pediatric tumors and causes
significant myelosuppression.
Anthracyclines are widely used for the treatment of solid tumors, leukemias,
and lymphomas, but side effects include myelosuppression and cardiotoxicity, which
presents as irreversible dilated cardiomyopathy that can be prevented with
dexrazoxane.
A common side effect of all antitumor antibiotics is alopecia.
Microtubule inhibitors
Microtubule inhibitors, as their name implies, disrupt the microtubules and
inhibit mitosis, which is a specific phase of the cell cycle. 
Anticancer agents in this class include the vinca alkaloids and the taxanes.
But first things first. The cytoskeleton is a network of proteins within the cell that
gives each cell its shape, and it anchors organelles in place.
But it's also a dynamic network, which can change shape when the cell wants to
move, contract, divide, or pull in or push out molecules. 
It’s made up of three proteins: actin filaments, intermediate filaments,
and microtubules. 
Microtubules are made of alternating round proteins called α- and β-tubulins, which
form long strands called protofilaments. 
Thirteen of these protofilaments come together to form a single microtubule. 
Microtubules play a super important role in cell division. 
During cell division there are two centrosomes inside the cell, and each centrosome
is made out of two centrioles. 
Each centriole is in turn made up of nine sets of microtubule triplets. 
Now cell division, or mitosis, can be divided into four
subphases: prophase, metaphase, anaphase, and telophase. 
During prophase, the membrane around the nucleus disintegrates, and the
chromosomes condense. 
During metaphase, chromosomes move towards the middle of the cell, on a line
called the metaphase plate.
Each chromosome is made up of a pair of sister chromatids which are joined
together in the centromere where there’s a specific protein complex called
the kinetochore. 
When the chromosomes are in place, each centrosome sends out thread-
like projectionscalled spindle fibers, that attach to the centromere of each
chromosome. 
Spindle fibers consist of microtubules that originate from the centrioles
and polymerize in the direction of the kinetochores.
Next, during anaphase, the centrosomes start pulling on the spindle fibers to pull the
sister chromatids apart, forming the mitotic spindle. 
It looks a bit like a fishing line being cast out to its target, and then the line gets
reeled in, pulling the kinetochore and it’s attached sister chromatid away from
its partnerchromosome.
Finally, there’s the telophase during which a nuclear membrane forms around each
new set of 46 single-chromatid chromosomes. 
After that, during cytokinesis, the cell membrane pinches in until the two daughter
cells separate. 
Alright, now cancer cells replicate rapidly so they are constantly
undergoing mitosis and the microtubules are always at work.
This means that microtubule inhibitors will affect these cells more than our healthy
cells, most of which only divide occasionally. 
Interfering with the formation of microtubules will cause mitosis to fail and the cell will
eventually die without replicating.
The two commonly used anticancer microtubule inhibitors include the vinca
alkaloids and the taxanes. 
All anticancer microtubule inhibitors are given intravenously. 
Okay, let’s start with vinca alkaloids, which include vinblastine, and vincristine. 
Vinca alkaloids bind to β-tubulin and block its polymerization into protofilaments,
which form microtubules, centrioles, centrosomes, and spindle fibers. 
This means the cell can’t form stable mitotic spindles and will stop at metaphase. 
So, vinca alkaloids act in the M phase of the cell-cycle and are cell-cycle specific. 
Moving on to indications. Vinca alkaloids are used for solid tumors like: breast
cancer; pediatric tumors like rhabdomyosarcoma and nephroblastoma or Wilms
tumor; and leukemias. 
Now, vincristine is also used for Hodgkin’s lymphoma, while vinblastine is used
for non-Hodgkin’s lymphoma. 
Let’s move on to side effects. Vinca alkaloids disrupt the progression of mitosis in all
rapidly dividing cells in the body including hair follicles and gastrointestinal
epithelium, so vinblastine and vinorelbine cause alopecia, or loss of hair,
and gastrointestinal symptoms. 
In addition, they are associated with bone marrow suppression since the cells here
are constantly making the platelets, red, and white blood cells.
Now, vinblastine causes more bone marrow suppression, but vincristine is more
neurotoxic, which usually manifests as peripheral neuropathy causing symptoms like
a decrease in sensation in the toes and fingers, sometimes called a glove and
stocking distribution, as well as autonomic nervous system malfunction
with orthostatic hypotension, urinary retention, and constipation. 
Alright, next are the taxanes, which are also alkaloid derivatives, and
include paclitaxel and docetaxel. 
Taxanes also act on microtubules, but they act differently from vinca alkaloids. 
They enhance tubulin polymerization into protofilaments and microtubules, but they
also bind directly to the spindle fibers and stabilize them. 
So they act like cement that overstablizes the microtubule and prevent them from
depolymerizing and breaking down. 
This is a problem because the microtubules need to break down during anaphase so
the cell can divide. 
So, taxanes are also cell-cycle specific and act on M phase. 
Moving on to indications. They are used for a variety of solid tumors including
breast, ovarian, lung, gastroesophageal, prostate, bladder, and head & neck
cancers. 
Side effects include alopecia, myelosuppression and neurotoxicity, which again
presents as a glove and stocking peripheral neuropathy. 
Also, they are associated with a possible hypersensitivity reaction during infusion.
Now, let’s make a simple and fun mnemonic that’ll help you
efficiently memorize these pharmacology facts about microtubule inhibitors. Okay, so
let’s imagine we are in ancient Rome and there’s a temple being constructed with
4 microtubule pillars. 
Now the first two pillars can’t be finished because there are vines growing all over
them, which represent the Vinca alkaloids. One vine plant has fruits that look like
little bombs for vinblastine, while the other has fruits that look like crystals
for vincristine. For indications, let’s use crabs to represent cancer, since in the
zodiac, cancer is a giant crab. Between the two pillars, there’s a solid, stone crab
statue to help you remember both drugs are used to treat solid tumors. On top of the
statue is a baby crab because they are also used for pediatric tumors like Wilms
tumor. Finally, the stone crab is carrying a giant bone club with little white crabs in
the bone marrow. This represents leukemia, which originates in the bone marrow.
For drug-specific indications, let’s use a hedgehog for hodgkin’s lymphoma, and this
little guy’s eating the crystal fruits from vincristine. Next, an unlucky hedgehog ate
the bomb fruits from vinblastine, and all his spines blew off, so he doesn’t look like
a hedgehog at all anymore, so he represents non-hodgkin’s lymphoma. To make
things worse, some of his bones also blew off and remain shattered on the ground,
which helps you remember vinblastine suppresses the bone marrow. 
For vincristine, let’s cover the little hedgehog’s legs in bandages to help you
remember the glove and stocking peripheral neuropathy. For the shared side effects,
we’ll have a baldman sitting by the statue for alopecia, he’s vomiting at the foot of the
statue which represents the GI side effects. 
Okay moving on to the taxanes which will be represented by two tax collectors by the
3rd and 4th pillar. One of them is a doe for docetaxel and the other is a pack mule for
pactaxel. They spent the money they collected on cement to make the pillars ultra
durable. Okay, for indications of these two drugs, let’s put another statue of
a stone crab between them since they are also used for solid tumors. This crab is
holding a pair of bras in one claw for breast cancer, and an egg in the other claw
for ovarian cancer, which are two of the most common uses. For side effects, let’s
have a janitor cleaning the statue. He’s also bald, for alopecia, and he’s sweeping
away some broken bones, which represents bone marrow suppression. His hands
and feet are wrapped in bandages for peripheral neuropathy, and there’s a syringe
sticking out of his arm which is covered in a red rash. This will help you remember
that these drugs can cause a hypersensitivity reaction at the injection site. 

Summary
All right, as a quick recap… Microtubule inhibitors such as vinca
alkaloids and taxanes are used as anticancer agents. 
Vinca alkaloids include vincristine and vinblastine. 
They work by binding to β-tubulin and blocking microtubule formation and thus the
affected cells are arrested in metaphase. 
They are used for the treatment of solid tumors, pediatric tumors, leukemias,
and lymphomas. 
Taxanes include paclitaxel and docetaxel and they work by over-
stabilizing microtubulesand preventing their break down during anaphase. 
Again, cells are arrested in metaphase, so both vinca alkaloids and taxanes are cell-
cyclespecific agents. 
Taxanes are used for the treatment of solid tumors like breast and ovarian cancers.
Platinum containing medication
Platinum containing agents, informally called platins, are a class of medications that
are used to treat cancer. 
They disrupt the structure of DNA by acting on consecutive guanine bases within a
strand of DNA and can affect all phases of the cell cycle.
Okay, now the cell cycle refers to the events that somatic cells, which includes all of
the cells in our bodies except the reproductive cells, go through from the moment
they're formed until the moment they divide into two identical daughter cells.
This cycle varies in length depending on the type of cell. For rapidly dividing cells,
like skin cells, it takes less than a day, whereas for other cells, like liver cells, the cell
cycle can last years. 
Now, the cell cycle can be divided in two phases: interphase and mitosis. 
Interphase comprises of the G1 phase, during which the cell grows and performs its
cell functions, the S phase, during which DNA is replicated, and the G2 phase,
during which the cell grows again before entering mitosis.
Mitosis can be broken down into prophase, metaphase, anaphase, and telophase,
during which the replicated DNA divides equally for the two daughter cells, and ends
with cytokinesis, which is when the cell membrane actually divides to form the two
new cells. 
There’s also a G0 phase which is an extended G1 phase, where the cell is resting
and not actively preparing to divide. 
Alright, now imagine a cancer cell. This cell is going through the phases of the cell
cyclewithout regulation, and its DNA also replicates more frequently, with less error-
correcting than healthy cells. Therefore, it’s more sensitive to DNA damage. 
Here’s a DNA base, guanine. Platinum containing agents attach at the number 7
nitrogen atom of two adjacent guanines on the same strand of DNA leading to the
formation of cross-bridges, or intra-strand cross-linking of the DNA. 
The resultant cross-linking inhibits DNA repair and prevents DNA from being
separated for replication, eventually leading to cell death. 
Platins are cell cycle-nonspecific agents, meaning they act on tumor cells during all
phases of the cell cycle, including the resting G0 phase. 
Platins are sometimes described as ‘alkylating-like’ agents as they act
like DNA alkylatingmedications, although they do not have an alkyl group.
Okay, platinum containing agents include cisplatin, carboplatin, and oxaliplatin,
which are all administered intravenously and eliminated through the kidneys. 
As their names imply, they are coordination complexes of platinum, meaning they
consist of a central atom of platinum and a surrounding array of bound molecules,
or ions, that are called ligands. 
Cisplatin has revolutionized the treatment of solid tumors. 
Today, cisplatin and carboplatin are used to treat a variety of solid tumors
including testicular, bladder, ovarian, cervical, and lung carcinomas. 
They are also used in the treatment of osteosarcoma, which is a common
malignant bone tumor in children and teens, which arises from osteoblasts. 
Oxaliplatin however, is only used in advanced colon cancer. 
Note that platins are eliminated unchanged through the kidneys.
Alright, moving on to the side effects. Platins can cause gastrointestinal
disturbances, including very severe nausea and vomiting, which can be prevented by
the use of ondansetron. 
It’s also seriously nephrotoxic, which is the main dose-limiting side effect. 
We can prevent nephrotoxicity with adequate hydration; diuresis using mannitol,
an osmotic diuretic; or saline, to prevent the medications from building up in the
kidneys. 
Nephrotoxicity seems to be related to reactive oxygen species, which are chemically
reactive compounds containing oxygen-like peroxides, superoxides,
and hydroxyl radicals. 
We can also use amifostine, a free radical scavenger, to prevent renal damage. 
Next, these medications are neurotoxic and can cause peripheral
neuropathy and ototoxicity due to acoustic nerve damage. 
The ototoxic effect usually presents as tinnitus or ringing in the ear and hearing loss. 
Finally, they can cause allergic reactions and mild bone marrow suppression, which
can lead to decreased platelets, red blood cells, and white blood cells.
Now, cisplatin causes the most severe nephrotoxic and neurotoxic side effects,
while carboplatin is more likely to cause bone marrow suppression. 
Oxaliplatin, causes even less ototoxicity. nephrotoxicity, and bone marrow
suppressionthan cisplatin or carboplatin.
Now, let’s make a simple and fun mnemonic that’ll help you
efficiently memorize these pharmacology facts about platinum-containing agents. So
first, let’s go to a music store where DJ Crabby-D’s album just went platinum. This
will help you remember that the platinum containing medications are used to treat
cancer. 
To celebrate, his sister coated herself in platinum, for cisplatin and she’s holding a
platinum coated cardboard box for carboplatin. 
Now she’s an MD, so behind her is a poster of the female reproductive system with
the ovaries and cervix circled, since cisplatin and carboplatin are used to treat
cervical and ovarian cancer. 
Another poster shows a man with his testicles, bladder, and lungs circled, to help
you remember these medications also treat testicular, bladder, and lung cancer.
Finally, under the posters is a scarecrow made of bones for osteosarcoma. 
Okay, so next let’s have her pet an ox, who’s also covered in platinum to
represent oxaliplatin. 
This ox has a large colon wrapped around him to help you remember it’s mainly
used to treat colon cancer. 
Okay, so the first fan to show up at the music store will represent the side effects,
and she’s wearing headphones for ototoxicity.
The headphones are also kidney shaped for nephrotoxicity. 
Next, her arms are all bandaged up, which represents peripheral neuropathy, and
her black T-shirt has a broken bone on it for bone marrow suppression. 
She partied too hard and vomited on the floor to represent the severe GI
disturbances these medications can cause. 
Summary
All right, as a quick recap…Platinum containing agents are a class of medications
used in the treatment of cancer. 
They are cell cycle-nonspecific agents, meaning they target all phases of the cell
cycle. 
Cisplatin and carboplatin can treat solid tumor malignancies
like testicular, bladder, ovarian, cervical, and lung carcinomas, while oxaliplatin is
used only in advanced colon cancer. 
Side effects of all platinum containing agents, which vary in frequency and intensity
for each drug, include nephrotoxicity, neurotoxicity, gastrointestinal
disturbances, myelosuppression, and allergic reactions.

Topoisomerase inhibitors
Topoisomerase inhibitors, as their name implies, are a class of medications that act
by blocking an enzyme called topoisomerase.
They are mainly used as anticancer agents that target specific phases of the cell
cycle. 
An interesting fact about these agents is that they are natural products, meaning
they are extracted from roots, plants, or trees.
But first things first. The cell cycle refers to the events that somatic cells - which
includes all of the cells in our bodies except the reproductive cells - go through from
the moment they're formed until the moment they divide into two identical daughter
cells. This cycle varies in length depending on the type of cell. 
For rapidly dividing cells, like skin cells, it takes less than a day, whereas for other
cells, like liver cells, the cell cycle can last for years. 
Now, the cell cycle can be divided into two phases: interphase and mitosis. 
Interphase comprises of the G1 phase, during which the cell grows and performs its
functions, the S phase, during which DNA is replicated, and the G2 phase, during
which the cell grows again before entering mitosis, or the M phase. 
Mitosis can be broken down into prophase, metaphase, anaphase, and telophase,
during which the replicated DNA divides equally for the two daughter cells, and ends
with cytokinesis, which is when the cell membrane actually divides to form the two
new cells.
Okay, so during DNA replication, we unzip the double helix with the enzyme DNA
helicaseand this creates a replication fork, with the two prongs of the fork
represented by the two strands that are separated from one another. 
Now, as DNA helicase unzips the DNA, the segments of DNA ahead of it start to
overwind - meaning, the double helix becomes more tightly wound. 
Overwinding of the DNA can slow down replication, so the enzyme DNA
topoisomeraseworks ahead of DNA helicase to loosen up the tight DNA coils. 
It achieves this by gently snapping one strand, loosening the overwinding tension,
and then patching it back up, tension free. 
Okay, so topoisomerase inhibitors are meant to interfere with both types
of DNAtopoisomerases, called topoisomerase I and II.
Topoisomerase I cuts one of the two strands of the double-stranded DNA during
replication, while Topoisomerase II cuts both strands. 
If we disable these enzymes, DNA will overwind just like a rubber band, until it tears
itself apart, leading to cell death.
Since cancer cells, in general, proliferate faster than healthy cells, they undergo DNA
replication more frequently and are more prone to the DNA damage caused
by topoisomerase inhibitors. 
Alright, now topoisomerase inhibitors are cell cycle-specific, or CCS, agents, and
they are the most active during the late S and early G2 phases of the cell cycle.
Okay, let’s start with camptothecins like irinotecan and topotecan, which are isolated
from the stems of the Camptotheca tree, also called happy tree, cancer tree, or tree
of life. 
They bind to and inhibit topoisomerase I and cause DNA damage during replication,
leading to cell death. 
Irinotecan is a prodrug, meaning that it needs to be metabolized into an active form
within the liver before it can produce the desired effect. 
In terms of elimination, irinotecan is excreted through bile and feces,
while topotecan is excreted through the kidneys, so the dose should be reduced in
people with impaired renal function. 
Now, irinotecan is used in metastatic colon cancer; and  topotecan is used for the
treatment of advanced ovarian cancer and for small cell lung cancer. 
The two most common side effects are myelosuppression, or depression of the bone
marrow function and gastrointestinal problems like diarrhea, but in general, these
medications have fewer toxicities than most other anticancer agents. 
Alright, next we have the podophyllotoxins like etoposide and teniposide, which are
derived from mandrake root, or Podophyllum peltatum. 
These medications induce DNA breakage through the inhibition of topoisomerase II. 
Elimination of teniposide and etoposide is mainly through the kidneys, which again
means that the dosage needs to be reduced in people with renal problems. 
Moving on to the indications, these agents are used in: solid tumors, particularly
in testicular and small cell lung cancer; in leukemia, which is a type of blood cancer
primarily affecting stem cells in the bone marrow; and in lymphomas, which usually
derive from lymphocytes in the lymph nodes. 
Okay, now common toxicities include myelosuppression, gastrointestinal
disturbances, and alopecia, or hair loss. 
Now, let’s make a simple and fun mnemonic that’ll help you
efficiently memorize these pharmacology facts about topoisomerase inhibitors. So
let’s start in a garden to remind us that topoisomerase inhibitors are natural, plant-
derived products. 
The garden is split into two parts by a fence. On one side, we can put topoisomerase
Iinhibitors, the camptothecins, which is represented by one happy tree and on the
other side we can put topoisomerase II inhibitors, the podophyllotoxins, which are
represented by two giant mandrakes. 
Okay, on the camptothecin side, let’s have two toucans, since these medications end
in “tecan.” Now one is lifting an iron dumbbell for irinotecan and the other is wearing
a top hat for topotecan. 
For indications, let’s use crabs to represent cancer, since in the zodiac, cancer is a
giant crab. So there’s a crab pinching the weightlifting toucan’s butt to help you
remember it’s used for colon cancer. The top hat toucan is guarding 2 eggs with little
crabs on them to represent ovarian cancer. On his hat, there’s another crab carrying
a tiny lung for small cell lung cancer. Under the tree, let’s have a dog digging up
some broken bones for bone marrow suppression. Unfortunately, the bones are very
dirty and they gave him diarrhea. 
Okay, let’s move on to the podophyllotoxin side of the garden. Here we’ll have
Poseidon guarding the mandrakes and he represents the medications that end with
“poside.” He is wearing a top hat again for etoposide, while holding a tennis racket
for teniposide. Okay, for indications, he’s sitting on a crab statue made
of solid stone since these medications treat solid tumors. There’s a tiny crab on its
head that’s carrying a tiny lung for small cell lung cancer. Next, poseidon is wearing
a jockstrap to help you remember testicular cancer. Instead of a trident, he’s holding
a giant bone club with little crabs in the marrow, which represents leukemia. There’s
also a little crab pinching a lymph node on his neck for lymphomas. The side effects
are very similar to camptothecins, so let’s use the dogdigging up the broken
bones for bone marrow suppression. This dog is vomiting to represent GI distress.
And finally, let’s give the dog a bald spot for alopecia.

Summary
All right, as a quick recap...Topoisomerase inhibitors are a class of plant-derived
medications that are used in the treatment of various types of cancer. 
They are cell cycle-specific agents and work by causing DNA damage by disabling
the DNA topoisomerase I or II. 
Irinotecan and topotecan inhibit topoisomerase I, and they are used
in colon, ovarian, and small cell lung cancer. 
In contrast, etoposide and teniposide inhibit topoisomerase II, and they are used
in testicular and small cell lung cancer, leukemia, and lymphoma.
Ribonucleotide reductase inhibitors
Ribonucleotide reductase inhibitors, as their name implies, are a class of
medications that act by blocking an enzyme called ribonucleotide reductase. They
are mainly used as anticancer agents that target a specific phase of the cell cycle. 
At a quick glance, the life of a cell - its cell cycle - has an interphase, made up of
subphases G1, S, and G2, during which the cell is preparing for division; and mitosis,
during which the cell actively divides.
During the S phase, the cell performs DNA replication - which is when its 46
chromosomes are duplicated so that each daughter cell can get its own copy of
the genetic material. 
Now, a single chromosome is made up of a single DNA molecule that has two
strands, which wrap around one another to form a double helix. 
Each single strand of DNA is composed of a sequence of DNA nucleotides. 
Now, nucleotides are the building blocks of nucleic acids such as deoxyribonucleic
acid, or DNA; and ribonucleic acid, or RNA. 
The most basic structure of the nucleotide can be broken down into three subunits; a
five carbon sugar, a phosphate group, and a nitrogenous base, also known as
a nucleobase. 
The five carbon sugar is either deoxyribose in DNA or ribose in RNA. 
Now, the nucleobases can be either pyrimidines or purines. 
The 3 pyrimidine bases are cytosine, or C; thymine, or T, which is DNA specific;
and uracil, or U, which is RNA specific. 
There are also two purine bases, adenine, or A; and guanine, or G. 
Now, if we link up just the sugar and the nucleobase, we've got ourselves
a nucleoside. 
To make a nucleotide, all we’ve got to do is add a phosphate group to the
5th carbon of the sugar on a nucleoside. 
Okay, so in order to make DNA nucleotides we use RNA nucleotides. 
RNA nucleotides are usually in the monophosphate form and we need to change
them into the diphosphate form for DNA. 
So a cytoplasmic enzyme called ribonucleotide reductase, also known as
ribonucleoside diphosphate reductase, will reduce the ribose within them into
deoxyribose, creating deoxyribonucleotides, which then travel to the nucleus
where DNA synthesis takes place. 
Alright, now the cancer cells are going through the phases of the cell cycle like
normal cells, but they divide much more frequently. 
Therefore, cancer cells replicate their DNA all the time and they need
more deoxyribonucleotides for this process. 
This makes them more sensitive to cytotoxic medications like the ribonucleotide
reductaseinhibitors, since they decrease the amount of
available deoxyribonucleotides. 
Ribonucleotide reductase inhibitors act in the S-phase of the cell-cycle, where
the DNAreplicates, and so they are cell-cycle specific. 
There are also normal tissues that divide rapidly like bone marrow and hair follicles,
which explains why these medications are more toxic to these tissues. 
Okay, ribonucleotide reductase inhibitors are a diverse group of medications and
include hydroxyurea, fludarabine phosphate, and gemcitabine. 
Let’s start with hydroxyurea, also known as hydroxycarbamide, which is
administered orally.
Hydroxyurea binds to the iron molecules in ribonucleotide reductase, which prevents
the enzyme from functioning. 
Hydroxyurea is used for myeloproliferative disorders, a group of disorders
characterized by proliferation of the bone marrow cells from the myeloid lineage,
like chronic myelogenous leukemia and polycythemia vera.
Hydroxyurea is also used for sickle cell disease because it stimulates the production
of fetal hemoglobin, or HbF, although the exact mechanism remains uncertain. 
Side effects include severe myelosuppression, presenting as leukopenia, macrocytic
anemia, and occasionally thrombocytopenia. 
Other side effects include gastrointestinal disturbances, pneumonitis, and mild skin
reactions. 
Hydroxyurea is also associated with minimal teratogenic effects but its safety during
pregnancy is not yet determined. 
Next is fludarabine phosphate, which is a fluorinated and phosphorylated analog of
the antiviral agent vidarabine. 
It can be administered either intravenously or orally.
In the plasma, fludarabine phosphate is rapidly converted into fludarabine, but then it
gets re-phosphorylated to a triphosphate derivative, which is the active form.
Fludarabine triphosphate directly binds to and inhibits ribonucleotide reductase, and
therefore blocks DNA synthesis. 
Additionally, fludarabine triphosphate incorporates into DNA and blocks DNA
polymerasewhich uses DNA as a template and starts adding nucleotides that are
complementary to form a new DNA chain. 
Moving onto indications, which include leukemias like chronic lymphocytic
leukemia and low grade lymphomas. 
Now side effects include myelosuppression, fever, and gastrointestinal disturbances
like nausea and vomiting. 
Let’s move on to gemcitabine, which is administered intravenously. 
When gemcitabine enters the cells, it undergoes phosphorylation and is converted
into a diphosphate form which binds to and inhibits ribonucleotide reductase. 
It also has a triphosphate form which can be incorporated into DNA and block DNA
polymerase.
Gemcitabine is indicated for a variety of carcinomas like pancreatic cancer, non-
small cell lung cancer, ovarian cancer, bladder cancer, and for non-
Hodgkin’s lymphoma. 
Now, side effects include myelosuppression, pulmonary toxicity, which presents
as pneumonitis, and a flu-like syndrome. 
Now, if gemcitabine is administered for a longer duration, it can lead to liver toxicity. 
Now, let’s make a simple and fun mnemonic that’ll help you
efficiently memorize these pharmacology facts about ribonucleotide
reductase inhibitors. So first, let’s set the scene at the beach next to a nuclear
power plant. The power plant tries to reduce their nuclear waste stockpile by
dumping them into the sea, and the tide carries them to the shore. This will help you
remember we’re talking about the ribonucleotide reductase inhibitors.
Now the first drug is hydroxyurea, so let’s have an ox drinking sea water to
keep hydrated, while also urinating into the ocean. 
There’s a pile of broken ox bones by him since a lot of his friends died drinking sea
water, and this represents the main side effect which is bone marrow suppression. In
fact let’s put broken bones all along the beach since all 3 ribonucleotide
reductase inhibitors share this side effect. 
The bones by this ox have tiny trees sprouting out from them since they got extra
nutrients from the ox’s urine, and they represent the main indication for hydroxyurea,
which is myeloproliferative disorders. There’s also a sickle sticking out from one of
the trees which represents the other indication, sickle cell disease. 
For the other side effects, let’s have a pregnant lady reprimanding the ox and she’ll
help you remember this medication is contraindicated during pregnancy. She’s got a
bad cough to represent the pulmonary toxicity and she also has a bad rash which is
another side effect.
Okay, so the owner of the ox is an Arabian man who flew in on a magic carpet and
he represents fludarabine. 
For indications, let’s use crabs to represent cancer, since in the zodiac, cancer is a
giant crab. So let’s have him holding a bone club with little crabs in the marrow to
represent leukemia. Also, a crab is pinching a lymph node on his neck for lymphoma.
He’s vomiting from the carpet to represent the GI side effects, and he’s also got a
thermometer in his mouth since he thinks he might have a fever. 
Okay, so trailing behind the man is his pet cheetah who’s wearing a gem-studded
collar since he represents gemcitabine. The lady caretaker of the cheetah is pulling
on its leash. She’s holding a frying pan that contains an egg and some crabs, which
represents pancreatic and ovarian cancer. 
Tied to the cheetah’s collar, there are two balloons; one looks like an
inflated bladder and the other looks like a lung, and there are crabs on the balloon so
you know they represent lung and bladder cancer. 
Finally for side effects, the woman is wearing an antiviral flu mask and she’s
coughing since gemcitabine causes flu-like symptoms and pneumonitis. The cheetah
is feasting on a big liver to help you remember that this medication could
cause hepatotoxicity. 
Summary
All right, as a quick recap… Ribonucleotide reductase inhibitors such
as hydroxyurea, fludarabine phosphate and gemcitabine are used as anticancer
agents. 
They work by inhibiting ribonucleotide reductase and blocking the formation
of deoxyribonucleotide. 
Since they prevent DNA synthesis, they act in the S phase and are cell-
cycle specific.
Hydroxyurea is used for the treatment of myeloproliferative disorders and for sickle
cell disease. 
Fludarabine phosphate is used for leukemias and lymphomas.
Gemcitabine is used for a variety of carcinomas and for non-Hodgkin’s lymphoma. 
A common side effect of these medications is myelosuppression. 
Hydroxyurea and fludarabine phosphate also cause GI disturbances. 
Hydroxyurea and gemcitabine cause pulmonary toxicity like pneumonitis. 
Long-term treatment with gemcitabine causes liver toxicity.
Skin cancer 2
Skin cancer is differentiated based upon the type of skin cell that's involved. 
There are three main types of skin cancer: basal cell carcinoma, squamous cell
carcinoma - collectively known as non-melanoma skin cancer, and melanoma. 
Diagnosis of skin cancer starts with naked-eye skin examination of the
characteristics of the lesion, as well as detailed history of the current skin complaint,
asking for the time of onset, duration, location, evolution, and symptoms. 
This is then followed by dermoscopy. Dermoscopy is a noninvasive, in vivo
technique used for the evaluation of skin lesions. 
It allows for the visualization of subsurface skin structures in the
epidermis, dermoepidermal junction, and upper dermis, which are otherwise
not visible to the naked eye. 
There are three dermoscopic criteria to predict malignancy of a pigmented lesion -
asymmetric distribution of colors and structures within a lesion, blue-white structures,
and atypical network. 
On the other hand, for nonpigmented lesions, the three criteria are ulceration, white
zones, and vascular structures and patterns. 
Now, the main purpose of dermoscopy in the evaluation of pigmented and
nonpigmented skin lesions to help decide whether or not to monitor the lesion
over time with sequential digital dermoscopy imaging to determine its biologic nature,
or to perform a skin biopsy, which is needed to confirm diagnosis of skin cancer,
showing the type of cells involved. 
Biopsy can also serve as the definitive treatment for lesions that haven’t spread
elsewhere. 
The three main types of skin biopsy are shave biopsies, punch biopsies, and
excisional biopsies. 
In shave biopsies, a superficial thin piece of skin is removed from the surface using a
small sharp blade, so they are typically used for lesions for which sampling of the full
thickness of the dermis is not necessary. 
On the other hand, punch biopsies involve the removal of a core-shape piece of
tissue using a sharp cutting tool, allowing to sample the deep dermis as well. 
Finally, excisional biopsies consist in the removal of an entire area of skin, including
the entire lesion and the portion of normal skin around it using a scalpel, and are the
preferred procedure for pigmented lesions.
The most common type is basal cell carcinoma, which involves cells in the stratum
basale. 
Basal cell carcinomas can appear as well circumscribed, pearly, waxy, or
shiny solid elevation of skin with small blood vessels running over it. 
Now, these tend to be slow growing tumors that rarely metastasize to distant regions
of the body or result in death, but can be locally invasive, spreading over several
centimeters of the epidermis. 
And they can break through the basement membrane and invade the dermis. In
fact, basal cell carcinomas can frequently become ulcerated. 
A skin biopsy shows how tumor cells on the periphery of islands typically arrange
themselves in a line, like fence-posts, forming a palisading pattern. 
The selection of appropriate therapy depends upon lesion characteristics such as
size, location, and pathologic features like aggressiveness. 
Whenever possible, the first choice for treatment is surgery, which is typically
performed in an outpatient setting. 
Surgical excision is the removal of a chunk of tissue using a scalpel, and the surgical
defect typically is immediately repaired either by side-side closure or the use of
adjacent tissue flaps or skin grafts. 
A major disadvantage of surgical excision is that it’s invasive, and variable amounts
of healthy tissue must be sacrificed to achieve acceptable cure rates, which may
lead to undesirable functional or cosmetic results. 
Re-excision is an appropriate option for incompletely excised lesions. 
Adjuvant radiotherapy is another option when surgical excision has been done
incompletely, as well as for the treatment of basal cell carcinoma in individuals who
are poor candidates for surgical intervention. 
Now, a specialized surgical technique is called Mohs micrographic surgery, or
simply Mohs surgery, in which the tumor is surgically excised and then immediately
examined under a microscope to verify sufficient margins before the surgical repair
of the site. 
If the margins are insufficient, more tissue is removed until the margins are
sufficient. 
This allows to control the tumor margins while minimizing the amount of normal
tissue that must be resected. 
Curettage and electrodesiccation may be an alternative treatment for individuals who
may not tolerate surgery or prefer not to undergo surgical excision. 
First, curettage is performed using a round knife, or curette, to scrape off the cancer
down to the dermis. 
Electrodesiccation is then performed by burning the exposed dermis with an electric
current. 
The curette is used again over the surgical ulcer to remove denatured dermis down
to living tissue, until achieving reasonable safety margins of curettage of normal skin
around the visible tumor. 
Finally there’s cryotherapy, which uses liquid nitrogen to freeze and destroy the
tumor. 
This technique is rarely used for treatment of skin cancer. 
Now, some superficial cancers may respond to topical therapy with 5% cream
or solution of fluorouracil, a chemotherapy agent, or 5% cream of imiquimod,
an immune response modifier. 
These agents must be applied for several weeks, and they may cause inflammatory
reactions. 
Finally, basal cell carcinoma may be treated with photodynamic therapy, which uses
photosensitizing porphyrins that are applied topically to the tumor, and the involved
area is then exposed to visible light. 
The light penetrates the skin and is selectively absorbed by the photosensitizer,
leading to tumor destruction. 
This technique is not often used, since risk of recurrence is pretty high compared to
the other treatment options. 
After successful treatment, individuals should be followed up at least once a year. 
The second most common type of skin cancer involves squamous keratinocytes, and
it can be further divided into three stages - actinic keratosis, Bowen’s disease,
and squamous cell carcinoma. 
First there’s actinic keratosis, which is a precancerous lesion
where keratinocytes are damaged by radiation and begin to over-produce keratin. 
Actinic keratosis can appear as dry, rough, almost sandpaper-like patches that are
surrounded by tan, brown, red or flesh coloredskin. 
They tend to commonly form on the lips, face, scalp, arm, ears, and the back of the
hands. 
Next there’s Bowen’s disease, which is an early stage of squamous cell carcinoma,
also called squamous cell carcinoma in situ. 
This usually appears as small, well-circumscribed, red elevations of the skin with
scaly plaques on top. 
At this point, the tumor can be found in the epidermis, but it has not broken through
the basement membrane. 
If squamous cell carcinoma becomes invasive, it can break through the basement
membrane and extend into the dermis, and it may even reach the hypodermis. 
As the lesion enlarges, the center becomes necrotic and may eventually turn into an
ulcer. 
Squamous-cell skin cancer is more likely to spread to regional lymph nodes or
distant areas than basal cell cancer. 
For that reason, a deeper biopsy including the subcutaneous tissue is necessary for
correct diagnosis. 
On skin biopsy, the keratinocytes are pleomorphic with hyperchromatic nuclei, and
numerous mitoses are present. 
Actinic keratoses have partial-thickness epidermal dysplasia, while Bowen’s disease
presents keratinocytic dysplasia involving the full thickness of the epidermis without
infiltration of atypical cells into the dermis, and finally, invasive squamous cell
carcinomas have dysplastic keratinocytes involving the full thickness of the
epidermis that penetrate the epidermal basement membrane to involve the dermis or
deeper tissues. 
The degree of cell differentiation may vary, becoming less and
less differentiated with more advanced disease. 
Treatment depends on the cancer stage. Actinic keratosis may be treated
with cryotherapy, topical therapy with fluorouracil or imiquimod, or photodynamic
therapy, to prevent its progression. 
On the other hand, standard surgical excision and Mohs surgery are the first line
treatment options for Bowen’s disease and invasive squamous cell carcinoma. 
Individuals with extensive perineural or large nerve involvement may also benefit
from the use of adjuvant radiotherapy, as well as those in which surgical margins are
positive, and those with one positive lymph node that’s no larger than 3 centimeters
with no extracapsular extension. 
On the other hand, more extensive lymph node involvement requires aggressive
surgical resection of the nodal basins. 
Non surgical treatments may be performed as second line options,
including curettage and electrodesiccation, cryotherapy, photodynamic therapy,
or radiotherapy alone. 
Topical therapy with fluorouracil or imiquimod may be used for the treatment
of Bowen's disease, especially for lesions that are larger than 3 centimeters
in diameter, and in situations in which healing after the other treatment options would
be compromised. 
Finally, systemic chemotherapeutic agents, such
as cisplatin, capecitabine, methotrexate, cetuximab, bleomycin, doxorubicin, and
the monoclonal antibody cemiplimab may be used in individuals with locally
advanced squamous cell carcinoma that cannot be adequately managed
with surgical excision or radiation therapy, as well as for metastatic squamous cell
carcinoma. 
And again, after getting successful treatment, individuals should be followed up at
least once a year. 
Finally, the most aggressive form of skin cancer is melanoma, which
involves melanocytes. 
Now, melanocytic nevus, more commonly known as a mole, results from a type
of melanocyte that over-produces melanin. 
These moles can be considered precancerous because they carry an increased risk
of becoming a melanoma. 
Melanomas grow horizontally within the epidermis and superficial dermis; and they
grow vertically - invading the dermis. 
Metastasis is most associated with the depth of invasion, and in fact, melanoma is
the deadliest form of skin cancer because of its tendency to metastasize quickly. 
The worrisome signs of melanoma can be remembered using the mnemonic ABCDE
where lesions are asymmetrically shaped, borders are irregular or notched,
coloration varies within the same lesion, the diameter is larger than 6 millimeters
across, which is roughly the size of a pencil eraser, and the lesion rapidly evolves
over time, quickly increasing in size, and can cause skin elevation. 
These features may be observed with the naked eye, and further examined through
dermoscopy. 
For definitive diagnosis, a complete full-thickness excisional biopsy of suspicious
lesions should be performed, an excisional biopsy taking a 1 to 2 millimeter margin
of normal-appearing skin and part of the subcutaneous fat should be performed for
lesions suspected to be a melanoma. 
Biopsy allows to determine the tumor thickness, as well as the characteristics of the
tumoral cells, which typically have large nuclei with irregular contours, and
produce melanin in a variety of colors: brown, red, dark blue, and gray. 
Finally, individuals should have their tumors assayed through molecular testing for
the presence or absence of a driver mutation at the V600 site in BRAF. 
If this turns out negative, they should have their tumor assessed for the presence of
a driver mutation in KIT.
If melanoma is confirmed, then this is usually followed up with a wider surgical
excision of the scar and surrounding normal tissue to reduce the risk of recurrence. 
The recommended width of surrounding local normal tissue is determined by
thickness of the primary tumor. 
In situ melanomas should get a 0.5 centimeter margin of normal tissue.
For melanomas smaller than 1 millimeter thick, the approach is to resect with a 1
centimeter margin of normal tissue. 
Finally, for melanomas larger than 1 millimeter thick, the approach is to resect at
least a 2 centimeter margin of normal tissue. 
Adjuvant radiotherapy may be considered to improve local control in individuals with
risk factors for local recurrence, such as tumors thicker than 4 millimeters, or those
presenting ulceration.
Now, lymphatic mapping and sentinel lymph node biopsy are indicated
for melanomas that are 0.8 millimeters thick or greater, and in those
with melanomas smaller than 0.8 millimeters if they present with ulceration. 
If sentinel lymph node biopsy turns out positive, we suggest careful clinical
observation coupled with ultrasound surveillance of the positive nodal basin. 
Complete lymph node dissection is indicated if there is subsequent evidence of
regional lymph node recurrence in the absence of distant metastases. 
Depending on the extent of lymph node spread, the individual will be considered for
adjuvant therapy. 
Individuals with microscopic involvement of a single lymph node may get
adjuvant immunotherapy with an anti-programmed cell death 1 or PD-1 agent, such
as nivolumab or pembrolizumab, while tumor that are positive for the BRAF V600
mutation may get MAPK pathway targeted therapy with the combination of
dabrafenib plus trametinib. 
On the other hand, individuals with macroscopic involvement of a lymph node, as
well as those with involvement of more than one node should get
adjuvant immunotherapy or targeted therapy. 
Finally, individuals who present with clinically apparent regional lymph node
involvement should get complete regional lymphadenectomy. 
And individuals at high risk of regional recurrence after lymph node dissection may
get adjuvant radiotherapy following surgery. 
This includes individuals with multiple positive nodes, extranodal spread, positive
surgical margins, and those with recurrent disease.
Finally, there’s no cure for metastatic melanoma, but these individuals may still get
palliative treatment to manage their symptoms, and to prolong survival. 
Individuals with one or a very limited number of metastases may benefit from
surgical metastasectomy, which means surgical excision of all metastatic disease
spots. 
On the other hand, non-surgical therapy is indicated for individuals in whom surgical
metastasectomy is not appropriate. 
This may involve radiotherapy or systemic therapy with medications
like immunotherapy, targeted therapy, or chemotherapy. 
Radiotherapy may have a palliative role for symptomatic localized areas of disease,
such as cerebral metastases, bone pain, spinal cord compression, and
symptomatic soft tissue metastases. 
As for systemic therapy, individuals without a V600 BRAF mutation may
get immunotherapy with pembrolizumab and nivolumab alone or in combination with
the anti-cytotoxic T-lymphocyte-associated protein 4 or CTLA-4 antibody
ipilimumab. 
On the other hand, individuals with a V600 BRAF mutation may get MAPK
pathway targeted therapy. 
Finally, individuals with a KIT mutation may be treated with the KIT inhibitor imatinib. 
Now, unlike immunotherapy and targeted therapy, cytotoxic chemotherapy has not
been shown to increase survival or to induce durable remissions. 
That’s why chemotherapy is generally given as a last resort to individuals who aren’t
suitable for further treatment with either immunotherapy or targeted therapy. 
Chemotherapeutic agents that may be used
include dacarbazine, temozolomide, carboplatin and paclitaxel which are given
together, or .

Summary
All right, as a quick recap… Skin cancer is differentiated based upon the type of skin
cell that’s involved into basal cell carcinoma, squamous cell carcinoma,
and melanoma. 
Diagnosis starts with naked-eye skin examination and detailed history, followed by
dermoscopy. 
To make a definitive diagnosis of skin cancer, a skin biopsy is needed, showing the
type of cells involved. 
Basal cell carcinoma involves cells in the stratum basale, and appear as well-
circumscribed, pearly, waxy, or shiny solid elevation of skin with small blood vessels
running over it. 
Treatment options include removal with surgery or with cryotherapy, where the tumor
is frozen off. 
Radiation, chemotherapy or immunotherapy may also be options. The first choice for
treatment is excisional surgery. 
Incompletely excised lesions may get re-excision or adjuvant radiotherapy. 
Individuals who may not tolerate or want to undergo surgery may get curettage and
electrodesiccation, photodynamic therapy, cryotherapy, or radiotherapy. 
Finally, some superficial cancers may respond to topical therapy
with fluorouracil or imiquimod. 
Next there’s squamous cell carcinoma, which involves squamous keratinocytes. 
Its early or in situ stage - called Bowen’s disease - usually appears as small, well-
circumscribed, red elevations of the skin with scaly plaques. 
As it grows, the center becomes necrotic and may eventually turn into an ulcer. First
line treatment is surgical excision. 
Adjuvant radiotherapy may be performed on individuals with extensive perineural or
large nerve involvement, as well as those in which surgical margins are positive, and
those with one positive lymph node that’s no larger than 3 centimeters with no
extracapsular extension. 
On the other hand, more extensive lymph node involvement requires aggressive
surgical resection of the nodal basins. 
Second line options include curettage and
electrodesiccation, cryotherapy, photodynamic therapy, or radiotherapy alone. 
Bowen's disease may get topical therapy with fluorouracil or imiquimod. 
Finally, systemic chemotherapeutic agents may be used for locally advanced or
metastatic squamous cell carcinomas. 
After treatment of non-melanoma skin cancer, individuals should be followed up at
least once a year. 
Finally, the most aggressive form of skin cancer is melanoma, which
involves melanocytes. 
The worrisome signs can be remembered using the mnemonic ABCDE where
lesions are asymmetrically shaped, borders are irregular or notched, coloration
varies, the diameter is larger than 6 millimeters across, and the lesion rapidly
evolves over time. 
First line treatment is surgical excision. 
Individuals with involvement of a single lymph node may get
adjuvant immunotherapy or targeted therapy. 
Finally, individuals who present with clinically apparent regional lymph node
involvement should get complete regional lymphadenectomy, followed by
adjuvant radiotherapy if there’s high risk of recurrence. 
Finally, metastatic melanoma may get palliative treatment, such as surgical
metastasectomy, radiotherapy or systemic medications like immunotherapy, targeted
therapy, or chemotherapy.
Neuroblastoma
Neuroblastoma is a type of tumor composed of “neuroblasts,” specifically neural
crest cells, which are cells involved in the development of the sympathetic nervous
system. 
Neuroblastoma is the most common cancer in infants, and it's only rarely seen in
children over five years old. 
When a fetus is in its 5th week of development, special cells called neural crest
cells start migrating along the spine. 
In the thoracic region of the spine, neural crest cells differentiate into the neurons of
the sympathetic chain, lying on either side of the entire spinal cord.
In the lumbar region, neural crest cells differentiate into the cells of the adrenal
medulla, the inner part of the adrenal gland that sits atop the kidneys. 
Together, the sympathetic chain and adrenal medulla form the sympathetic nervous
system, connecting the brain and central nervous system to various organs including
the heart and blood vessels. 
So, when you’re under some sort of stress, like playing a competitive sport like
badminton, the sympathetic nervous system kicks into action. 
The sympathetic neurons releases norepinephrine, also called noradrenaline, and
the cells of the adrenal medulla release norepinephrine and epinephrine, also
called adrenaline. 
These hormones bind to receptors in various tissues like the blood vessels, the
heart, and the lungs, redirecting blood flow to your muscles, make your
heart pump faster, and expanding the airways in your lungs, all of which can help
you make the winning hit. 
After the game is over, and the hormones are no longer
needed, epinephrine and norepinephrine break down into metabolites
like homovanillic acid or HMA, and vanillylmandelic acid, or VMA. 
In neuroblastoma, some neural crest cells in the sympathetic chain or adrenal
medulla don’t differentiate properly during fetal development, and these cells
ultimately go on to form a tumor, which most often form in the adrenal medulla, but
can also develop in other areas of the sympathetic chain. 
While no one knows exactly how it happens, this abnormal cell differentiation has
been associated with mutations in the
MYCN oncogene, Anaplastic lymphoma kinase ALK fusion oncogenes, and
mutations in tumor suppressor genes, like the Paired-like homeobox 2b or PHOX2B,
and other tumor suppressor genes on chromosome 1 and 11. 
Oncogenes help cells grow and proliferate, while tumor suppressor genes slow down
cell growth and proliferation. 
So both an MYCN amplification or ALK gene fusion, where the oncogene is “turned
on,” or a PHOX2B and chromosome 1 and 11 deletions, where tumor suppressor
genes are “turned off,” can potentially cause uncontrolled cell growth. 
There are three types of neuroblastomas, and they’re categorized based on the size
and shape of the tumor cells: undifferentiated, poorly differentiated, and
differentiating neuroblastoma.
An undifferentiated neuroblastoma is mostly comprised of neural crest cells, which
are sometimes called small round blue cells, due to a lack of cytoplasm, and a large
blue nuclei. 
A poorly differentiated neuroblastoma is composed of slightly more differentiated
cells, with smaller nuclei and a bit more cytoplasm. 
In addition, the cells of a poorly differentiated neuroblastoma may be surrounded by
a substance called neuropil, which is a dense network of interwoven nerve fibers,
like axon and dendrite branches. 
Finally, a differentiating neuroblastoma is composed of cells with lots of cytoplasm,
and is often surrounded by a substance called Schwannian stroma. 
Schwannian stroma is a connective tissue from non-neuronal cells that forms myelin,
which insulates the axons of the mature neurons. 
When any type of neuroblastoma forms, cells in the surrounding tissue
release chemokines called CXCL12 and that stimulates nearby immune cells. 
CXCL12 is normally produced by some organs like the lymph nodes, liver, bones,
and especially the bone marrow, but gets produced in higher amounts when tissue is
damaged.
When immune cells sense high levels of CXCL12, they get stimulated and move
towards the area where it’s coming from. 
As it turns out, neuroblastic tumor cells also get stimulated by CXCL12. 
If a neuroblastoma cell breaks away and gets into the blood or lymph, it will
sometimes migrate towards the organs where CXCL12 is normally produced -
creating metastatic tumors there.
Symptoms of neuroblastoma result from the chemokine release, and include fever,
weight loss, sweating, and fatigue.
Other symptoms of neuroblastoma depend on where the tumor is located, and are
usually a result of the tumor pressing up against surrounding organs. 
For example, if the tumor is in the thoracic region of the sympathetic chain, it can
grow into the lungs, causing breathing difficulties. 
A thoracic tumor that extends to the neck can press up against nerves originating
there and heading towards the face, and it can cause Horner syndrome. 
Horner syndrome involves miosis or constriction of the pupils, ptosis or the drooping
of the eyelid, and anhidrosis which is an inability to sweat in the face. 
Tumors on the sympathetic chain might also grow into the spine,
causing neurologic symptoms, like muscle
weakness or boweland bladder problems. 
Children with a tumor in the adrenal medulla can have a large, painful abdominal
mass that causes abdominal swelling.
About half of all neuroblastomas spread to the bones, causing bone pain and small
fractures. 
Classically, neuroblastomas can cause fractures at the base of the skull, just where
the skull connects to the spine. 
With these fractures, fluid and blood to leak into the tissues around the eyes. When
that happens it can cause periorbital ecchymosis, also called raccoon eyes, because
of the dark rings of blood that can be seen in the soft tissue around the eyes. 
Neuroblastoma that invades the bone marrow can also affect the marrow’s ability to
make healthy red blood cells, platelets, and white blood cells, leading to fatigue,
easy bruising, and frequent infections. 
Diagnosis of neuroblastoma usually starts with testing for HMA and VMA in the blood
or urine, since high levels those metabolites may indicate tumors that
secrete epinephrine and norepinephrine.
A CT scan can show the location and size of the tumor, and a complete blood
count can help determine whether neuroblastomahas spread to the bone marrow. 
Treatment largely depends on the size and staging of the neuroblastoma--meaning
how far the tumor has spread. 
Early on, surgery can be used to remove the tumor, but once it has started to spread
it might require a combination of chemotherapy, medication, and even a stem-
cell or bone marrow transplantation. 
Generally speaking, the best treatment outcomes are among the youngest patients
that have a differentiating neuroblastoma.

Summary
Alright, as a quick recap, neuroblastoma is a condition where neural crest cells of the
developing sympathetic nervous systemand adrenal medulla do not differentiate
normally. 
Rather, they continue to proliferate in an immature state, creating tumors that press
on nearby organs, or spread to other organs causing complications like horner
syndrome and raccoon eyes. 
High levels of HMA and VMA are usually the first indication of neuroblastoma.
Tumor wilms
Wilms' tumor, or nephroblastoma, is a type of kidney tumor composed of
metanephric blastemal cells, cells involved in kidney development, and is the most
common malignant kidney tumor in children; only rarely is it seen in adults.
Wilms’ tumor is thought to be caused by mutations in genes responsible for normal
genitourinary development, which includes the kidneys as well as the gonads,
typically the genes are located around 11p13—which means chromosome 11,
the short armp, region 1, band 3. 
One gene critical for normal kidney and gonad development is WT1 (or Wilms’
Tumor 1), which a tumor suppressor gene. 
Mutations that result in a “loss of function” of WT1, like deletions, for example, seem
to lead to the development of tumor cells seen with Wilms’ tumor. 
Wilms’ tumors as a result of WT1 mutations are sometimes part of a developmental
syndrome, meaning other abnormalities are present as well, likely because of
deletion or mutation of other genes in addition to WT1. 
For example, in WAGR syndrome, a mutation in the 11p13 region causes deletion of
both WT1 and the PAX6 genes, among others, which leads to Wilms’ tumor and
Genitourinary malformations as a result of WT1 deletion, as well as Aniridia (which is
absence of iris) and intellectual disability (which is formerly referred to as mental
Retardation), as a result of PAX6 deletion.
Another syndrome associated with WT1 mutations is Denys-Drash syndrome, which
is characterized by Wilms tumor, early-onset nephrotic syndrome, and male
pseudohermaphroditism.
Another gene, WT2, also located on chromosome 11, seems to also be involved with
other Wilms’ tumor-containing syndromes, like Beckwith-Wiedemann syndrome,
which includes Wilms’ tumor, macroglossia, organomegaly, and hemihypertrophy.
All that being said, Wilms’ tumor, in the majority of cases, happens in otherwise
healthy children, and doesn’t seem to be associated with WT1 or WT2, or any
developmental syndrome of any kind. So in those situations, the mechanism of
tumor development is not well understood. 
Regardless of what the exact cause of the tumors are, they’re usually composed
partly of metanephric blastemal cells, which are cells that give rise to other cells
like stromal cells, which are the connective tissue cells, as well as epithelial cells, all
of which that normally help give rise to structures in the kidney. 
That being said, in this mass there are usually abortive or partly-developed
structures of the nephron—like glomeruli and tubules. A tumor composed of
blastemal, stromal, and epithelial cells is called a triphasic blastoma.
Children with Wilms’ tumor often present with a flank mass that’s large, palpable,
and unilateral, and they also sometimes have hematuria—blood in the urine, as well
as hypertension as a result of renin secretion.
Treatment depends on the extent of spreading of Wilms’ tumor, although the overall
prognosis is very good, and people with Wilms’ tumor often respond well to a
combination of nephrectomy—removal of the kidney, and chemotherapy.

Summary
Alright, so quick recap, Wilms’ tumor’s typically affects children and usually the
cause is unknown, though sometimes it can be caused by gene mutations,
specifically WT1 and WT2, and the tumor mass, or “triphasic nephroblastoma” is
composed of blastema cells, stromal cells, and epithelial cells.
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Hepatocellular carcinoma
As opposed to benign hepatic tumors, malignant hepatic tumors are cancerous, very
severe, and are actually now the third leading cause of cancer deaths worldwide. 
With these malignant liver cells or hepatocytes, just like malignant cells in other
cancers, they develop some mutation that causes them to replicate at way higher
rates and form these masses of cells that continue to grow and potentially spread to
other tissues.
This would be a primary hepatic tumor, since it starts in the liver. It's totally possible,
though, for liver tumor to develop as a metastasis from another primary cancer, in
which case it would not be hepatocellular carcinoma, but a carcinoma from
somewhere else, and this is actually more common than primary liver
tumors themselves. 
The most common sources of the tumor cells that got to the liver but started
somewhere else are the colon, pancreas, lung and breast. 
What exactly causes the mutation in the hepatocyte though?
Well the mechanism isn’t fully understood and can probably be caused by a lot of
different things, most importantly though, things that put the liver in a constant cycle
of damage and repair are the biggest culprits.
If the liver cells are constantly being forced to repair, this raises the chances of
genetic mistakes or mutations, potentially leading to carcinogenesis or development
of cancer cells. 
Examples might be any disease that leads to cirrhosis and scarring of the liver
tissue, which can include alcoholic hepatitis and cirrhosis,
hereditary hemochromatosis, primary biliary cirrhosis, alpha-1 antitrypsin deficiency,
and others.
The most common risk factor, the ones that have been linked the most
with hepatocellular carcinoma are the hepatitis B and hepatitis C viruses, both of
which can become chronic or long-lasting. 
In this case, these cells are at greater risk because of the constant state of infection
and immune cell attack, leading to constant damage and repair. 
HBV is particularly problematic because of how the virus replicates; the HBV virus is
a DNA virus that integrates into the hepatocyte’s DNA, which, although not
completely understood, is thought to either directly disrupt regulation of cell growth
and replication, leading to carcinoma, or alternatively cause some indirect effect that
later leads to unchecked cell growth and replication. 
One interesting risk factor, is exposure to aflatoxins. 
Aflatoxins are highly toxic chemicals produced by certain aspergillus molds that can
be found in certain foods when they start to decay, like grains, peanuts, and
vegetables. 
As foods that have this type of mold are eaten, aflatoxins are also eaten, and then
they’re absorbed in the small intestine and sent to the liver for metabolizing. 
The most potent type of aflatoxin thought to be involved in carcinogenesis is aflatoxin
B1, and when it gets to the liver, it’s metabolized to aflatoxin B1 8,9 epoxide. 
And now this guy can bind right to DNA, called a DNA adduct. 
This interaction leads to mutations in the  p53 tumor suppressor gene, which usually
when it’s functioning right, stops the formation of tumors, so if it becomes mutated
and dysfunctional, tumor formation and carcinogenesis might follow.
Because most patients with hepatocellular carcinoma also have cirrhosis,
the hepatocellular carcinoma can be hard to spot. 
Symptoms of long-standing liver disease like cirrhosis often masks the progression
of carcinoma, and often patients have no symptoms directly related to the tumor
itself.
A delay in detection of any disease typically means a worse prognosis,
and hepatocellular carcinoma is no exception. 
In general, the cancer may be focal, or limited to one area, but it might also have
several areas affected and be multifocal, or it could also spread diffusely through the
liver tissue and not really have distinct focal points. 
A classic sign of a secondary hepatic tumor, though, are multiple focal points that
can even be sometimes felt on the free edge of the liver. 
A common place for the tumor to spread is in the portal and hepatic veins, where a
mass of tumor cells might lodge and block the veins. 
If the hepatic vein is blocked, pressure builds in the portal system, pushing fluid into
the peritoneal cavity and leading to abdominal swelling, called ascites, and
perhaps hepatomegaly, enlargement of the liver. 
This blockage of the hepatic vein is also known as Budd-Chiari syndrome. 
Because their abdomen’s swollen from ascites and hepatomegaly, patients might
present with abdominal pain as well as fever due to the destruction of liver cells. 
Having said that, a relatively large proportion of patients though, about one third, are
asymptomatic, and as such the cancer is found incidentally.
On histology, it’s common to see bile inside the hepatocytes as well as the smaller
cancerous hepatocytes invading the spaces around larger normal hepatocytes. 
Also, in the blood, a bigtime indicator is an increase in alpha fetoprotein, or AFP. 
AFP’s normally found in abundance in fetal plasma, and drops off to smaller
amounts in adulthood. AFP’s also produced by the tumor or proliferating cells, so as
the tumor cells proliferate, more AFP than normal can be found in the blood. 
Also though, blood ALP and GGT will be increased as well, both of which are
enzymes typically found in the liver that can be released after liver cell damage.
Finally, some additional proteins can also be elevated, like erythropoietin, which
controls the proliferation of red blood cells, insulin-like growth factor, which promotes
cell proliferation, and parathyroid hormone-related protein which can be secreted in
higher-than-usual amounts by tumor cells.
Imaging procedures can be helpful in making a diagnosis, like CT scans, ultrasound,
and particularly angiography which can help show vascularity. 
If the tumor’s found and can be surgically removed, which is about 20% of cases,
then the survival rate is improved by quite a bit, but if it’s not able to be removed,
then survival is much lower, in the range of months to years. 
Typically radiation and chemotherapy have been shown to not be super effective, but
certain patients might be candidates for liver transplant.
If the cancer’s able to metastasize and get into the bloodstream, it most commonly
goes to the lungs as the secondary organ.

Non Hodgkin lymphoma

The term non-Hodgkin lymphoma, sometimes called NHL, can be broken down.
Lymph- refers to lymphocytes and oma- refers to a tumor. 
“Non-Hodgkin” refers to the absence of a key cell that's seen in Hodgkin lymphoma,
the  Reed-Sternberg cell. 
So, non-Hodgkin lymphoma is a tumor derived from lymphocytes - specifically B-
cells and T-cells, which mainly live in the lymph nodes and move through the blood
and lymphatic system. 
Now, B-cell development begins in the bone marrow, which is a
primary lymphoid organ. That’s where young precursor B-cellsmature into naive B-
cells. 
The naive B cells then leave the bone marrow and circulate in the blood and
eventually settle down in lymph nodes. 
Humans have hundreds of lymph nodes, scattered throughout the body, and they’re
considered secondary lymphoid organs. 
Each lymph node has B-cells which group together in follicles in the cortex or outer
part of the lymph node, along with T-cells in the paracortex just below the cortex. 
B-cells differentiate into plasma cells, which are found in the medulla or center of the
lymph node. 
Plasma cells release antibodies or immunoglobulins. 
Antibodies bind to pathogens like viruses and bacteria, to help destroy or remove
them. 
Various immune cells, including B-cells have surface proteins or markers that are
called CD, short for cluster of differentiation, along with a number - like CD19 or
CD21.
In fact, the combination of surface proteins that are on an immune cell works a bit
like an ID card. 
Now, a B cell is activated when it encounters an antigen that binds just perfectly to
its surface immunoglobulin. 
Some of these activated B-cells mature directly into plasma cells and produce IgM
antibodies.
Other activated B-cells go to the center of a primary follicle in the lymph node and
they differentiate into B-cells called centroblasts and start to proliferate or divide.
These proliferating centroblasts form a germinal center, located in the center of the
follicle of the lymph node. 
These centroblasts have a rearrangement of their immunoglobulin genes, and some
of them undergo a class switch where they change from producing IgM antibodies to
producing IgG or IgA antibodies. 
Within the germinal center, centroblasts mature into centrocytes; and the centrocytes
that make antibody with high affinity for the antigen, differentiate into either plasma
cells which go to the medulla or memory B-cells which circulate in the blood and
reside in lymph nodes, spleen, and mucosa-associated lymphoid tissue, also called
MALT. 
Now, T-cell development starts in the thymus from precursors that arise in the bone
marrow. 
In the thymus, these precursor T-cells mature and express either CD4 on helper T-
cells or CD8 on cytotoxic T-cells sometimes known as suppressor T cells.
Mature T-cells circulate in the blood and are found in the paracortex of the lymph
nodes. 
In non Hodgkin lymphoma, there is usually a genetic mutation in a lymphocyte -
either a B cell or a T cell. When something like that happens, cells are supposed to
undergo apoptosis - or programmed cell death, but instead the lymphocyte starts to
divide uncontrollably - becoming a neoplastic cell.
Usually, lymphomas develop in lymph nodes and they’re called nodal lymphomas. 
Lymphomas can happen anywhere in the body, though, and when they develop in
other tissues or organs - like the stomach or skin - they’re called
extranodal lymphomas. 
Lymphoma cells can also get into the blood and can spread to other parts of the
body. 
If lymphoma cells get into the gastrointestinal tract they can grow and cause bowel
obstruction. If they go to the bone marrow, they can crowd out normal bone
marrow progenitor cells and decrease the number of healthy red blood cells, white
blood cellsand platelets. If they go to the spinal cord they can cause spinal
cord compression. 
Now, the two main groups of Non-Hodgkin lymphomas are B cell and T
cell lymphomas. 
B cell lymphomas are more common and the neoplastic B cells usually express
CD20 on their surface.
And there are various types of B cell lymphomas and an important feature is how
quickly each one grows- they can be indolent or slow to grow, aggressive, or highly
aggressive. 
The first type of B cell lymphoma is a diffuse large B cell lymphoma, this type is the
most common and it’s an aggressive lymphoma. 
A second type of B cell lymphoma is a follicular lymphoma, and it’s an
indolent lymphoma. 
One known mechanism for how a follicular lymphoma develops, is a chromosomal
translocation between chromosome 14 and chromosome 18. 
In the translocation, the two chromosomes swap large pieces of chromosome with
each other. As a result the BCL2 gene from chromosome 18 is placed after
the immunoglobulin heavy chain promoter on chromosome 14, and that results
in overexpressionof bcl-2. 
Bcl-2 normally blocks cell death, or apoptosis, so overexpression of the bcl-2
gene prevents the cell from dying. 
A third type of B cell lymphoma is Burkitt lymphoma, and it’s a highly
aggressive lymphoma. 
Burkitt lymphoma can also result from a chromosomal translocation. In this case,
the Myc gene is translocated from chromosome 8 where it ends up adjacent to
IgH promoter on chromosome 14 and again that upregulates its expression. 
The Myc gene stimulates cell growth and metabolism, so the translocation results in
increased cell division. 
In individuals in Africa, Burkitt lymphoma classically causes extranodal involvement
of the jaw and is often associated with Epstein Barr virus infection. 
In contrast, in individuals outside Africa, Burkitt lymphoma classically causes
extranodal involvement of the abdomen - most often at the ileocecal junction - and is
less frequently associated with Epstein Barr virus infection. 
Epstein Barr virus infects lymphocytes and can incorporate its DNA into a host
cell’s DNA, but exactly how that leads to lymphoma is still unclear. 
Under the microscope, Burkitt lymphoma is said to have a "starry sky” appearance.
That’s because there are a few “tingible bodies” which are macrophages that have
eaten up dead neoplastic cells that look like little stars. And these are scattered
among lots of neoplastic lymphocytes that look dark like the night sky. 
A fourth type of B cell lymphoma is mantle cell lymphoma, and this one’s an
aggressive lymphoma.
Mantle cell lymphoma can also result from a chromosomal translocation. In this
case, the BCL1 gene from chromosome 11 ends up next to the
immunoglobulin promoter on chromosome 14, which again upregulates its
expression.
The BCL1 gene encodes the protein cyclin D1, which stimulates cell growth, so once
again the translocation results in increased cell division. 
A fifth type of B cell lymphoma is marginal zone lymphoma, and it’s an
indolent lymphoma. 
The most common type is marginal zone lymphoma of mucosa-associated lymphoid
tissue or MALT. This type is extranodal - mostly happening in the lining of the
stomach among individuals with chronic inflammation, like those with Helicobacter
pyloriinfection, a bacteria that causes chronic gastritis. 
There’s also nodal marginal zone lymphoma, which happens within lymph nodes,
and splenic marginal zone lymphoma which happens in the spleen. 
A sixth type of B cell lymphoma is lymphoplasmacytic lymphoma, and this one’s also
an indolent lymphoma. 
This form of lymphoma often involves the bone marrow, lymph nodes, and spleen,
and the neoplastic cells sometimes produces immunoglobulins, called “M proteins,”
that are found at high levels in the blood. 
When this happens, the additional proteins in the blood cause the blood to be more
thick and viscous and the condition is called Waldenstrom macroglobulinemia.
The other group of non Hodgkin lymphomas are the T cell lymphomas. 
The first T cell lymphoma is adult T-cell lymphoma, but it’s sometimes referred to as
a leukemia because the abnormal white blood cells or leukocytes often get into the
bloodstream. 
Adult T-cell lymphoma is thought to be caused by the human T-lymphotropic virus or
HTLV, which spreads through body fluidsand infects T cells. 
HTLV incorporates its DNA into T cell DNA and causes a genetic mutation in the
process, and that leads to adult T-cell lymphoma. 
The second T cell lymphoma is mycosis fungoides which is a T cell lymphoma of the
skin that causes patches on the skin that looks a bit like a fungal infection. 
The neoplastic cell in mycosis fungoides is a CD4+ helper T-cell, and under
a microscope it has a distinctive “cerebriform” nucleus because it looks like a brain. 
If these neoplastic CD4+ helper T-cells start to circulate in the blood, they can cause
Sezary syndrome, which is when there’s a generalized red
rash called erythroderma or itchy skin. 
For symptoms, individuals with non-Hodgkin lymphoma usually develop
painless lymphadenopathy. 
The release of cytokines causes symptoms like fever, drenching night sweats, and
weight loss. 
If there’s extranodal involvement of the gastrointestinal tract, it can cause bowel
obstruction. 
If there’s extranodal involvement of the bone marrow, it can cause fatigue,
easy bruising, or recurrent infections. 
And if there’s extranodal involvement of the spinal cord, it can cause weakness and
a loss of sensation - usually in the legs. 
Identifying non Hodgkin lymphoma often begins with imaging studies, like a CT scan,
which can help establish the stage of the lymphoma.
The staging is based on the extent of nodal and extranodal involvement. And finally
a lymph node biopsy is required for diagnosis.
Treatment options for non-Hodgkin lymphoma mainly consists of chemotherapy
and radiation therapy, and depend on things like the lymphoma subtype, whether it’s
indolent, aggressive, or highly aggressive, and how far it has spread. 
If the lymphoma has CD20-positive B-cells, Rituximab can also be used. 
Rituximab is a monoclonal antibody that binds CD20 and induces complement-
mediated lysis, as well as direct cytotoxicity and apoptosis.

Summary
All right, as a quick recap, non-Hodgkin refers to the absence of “Reed-sternberg
cells” which are characteristic of hodgkin lymphoma.
Non-hodgkin lymphomas can originate from B cells or T cells, though they most
commonly arise from B cells. 
Diffuse large B-cell lymphoma is the most common type of non-Hodgkin
lymphoma among adults, and follicular lymphoma is the most common indolent or
slow-growing non-hodgkin lymphoma. 
T cell lymphomas include adult T-cell lymphoma, which is sometimes referred to
as leukemia, as well as mycosis fungoides.
Anatomy of breast
The breasts are the most prominent superficial structures in the anterior thoracic
wall consisting of glandular tissue and a supporting fibrous and fatty matrix. 
This glandular tissue, or mammary glands, are found in the subcutaneous
tissue overlying the pectoralis major and minor muscles. 
The amount of fat surrounding this glandular tissue will determine the size of the
breasts. 
Breasts have a circular body and a nipple in the center, surrounded by a pigmented
area of skin called the areola. 
Each breast has the following boundaries: transversally from the lateral border of
the sternum to the midaxillary line and vertically from the second through the
sixth ribs. 
Two thirds of the underlying tissue of the breast is formed by the
pectoral fascia covering the pectoralis major and the other third is formed by
the fascia that covers the serratus anterior muscle. 
A small part of the breast might extend along the inferolateral edge of the pectoralis
major, going towards the axillary fossa or the armpit. 
Here it forms an axillary process or tail, called the tail of Spence. 
Now, let's take a look at this sagittal section of the female breast. 
As you can see, there’s a fine space between the breast and the pectoral fascia. 
This is called the retromammary space or bursa, which is a loose subcutaneous
tissue plane. 
This plane contains a small amount of fat which allows the breast to move a bit on
the pectoral fascia. 
Breasts contain the mammary glands responsible for lactation in females. 
Mammary glands are made up of 12 to 20 lobes, each of them containing many
smaller lobules. 
These smaller lobules have grape-like clusters of alveoli that
contain mammary secretory epithelial cells, the milk producing cells of lactation. 
These alveoli, lobules and lobes are connected through a network of ducts called
the lactiferous ducts, and eventually form a unique lactiferous duct for each lobe
which opens independently to the areola to drain the milk produced during lactation. 
Each lactiferous duct has a dilated portion deep to the areola called
the lactiferous sinus in which there’s a small drop of milk that accumulates or
remains in a nursing mother, which becomes expelled from the areola when
compressed during feeding.
Next, the stroma of the breast is composed of adipose tissue and fibrous connective
tissue. 
In a non-lactating state, the adipose tissue is situated between the lobes and makes
up most of the breast volume. 
The fibrous connective tissue of the stroma goes on to form fibrous condensations,
called the suspensory ligaments of Cooper, which firmly attach the mammary
glands to the dermis of the overlying skin. 
These fibrous connective tissue attachments help support the lobes and lobules of
the mammary glands. 
Moving on, the areolae surround the nipples, which are typically located around the
4th intercostal space lateral to the mid clavicular line; but this varies depending on
the size of the breast. 
Each areola contains a large number of sebaceous glands, which get bigger during
pregnancy and secrete an oily substance that acts as a lubricant for
the areola and nipple. 
The nipples are conical or cylindrical prominences in the centers of the areola. 
Keep in mind that nipples have no fat, hair, or sweat glands. 
The lactiferous ducts open into the tips of the nipples. 
Structurally, the nipples are composed of circularly arranged smooth muscle
fibers that compress the lactiferous ducts to help express milk during lactation. 
Now let’s look at the arterial supply of the breast, which derives from several arteries:
the medial mammary branches, the lateral thoracic artery, the thoraco-
acromial arteries and posterior intercostal arteries. 
The medial mammary branches come from the internal thoracic artery which
originates from the subclavian artery. 
The lateral thoracic and thoraco-acromial arteries are branches of the axillary artery. 
The posterior intercostal arteries are branches of the thoracic aorta in the 2nd, 3rd,
and 4th intercostal spaces. 
Finally, the veins of the breast mainly drain into the axillary vein, but some also drain
to the internal thoracic vein . 
Let’s move on to the lymphatic drainage of the breast. 
Basically, lymph passes from the nipple, areola and glandular lobules to
the subareolar lymphatic plexus. 
From here, most lymph,especially from the lateral breast quadrants, initially drains to
the anterior or pectoral nodes and then to the axillary lymph nodes. 
Sometimes, some lymph may drain directly to other axillary nodes or even to
interpectoral, deltopectoral, supraclavicular or inferior deep cervical nodes. 
The remaining lymph, especially from the medial breast quadrants, drains to the
parasternal lymph nodes or to the opposite breast. 
Lymph from the inferior quadrants may pass deeply to abdominal lymph nodes,
specifically to the subdiaphragmatic inferior phrenic lymph nodes. 
Lymph from the skin of the breast, with the exception of the nipple and areola, drains
into the ipsilateral axillary, inferior deep cervical, and infraclavicular lymph nodes and
also into the parasternal lymph nodes of both sides. 
Lymph from the axillary nodes first drains into the clavicular lymph nodes and then
into the subclavian lymphatic trunk. 
And finally, lymph from the parasternal nodes enters the
bronchomediastinal lymphatic trunks which goes on to eventually drain into the
venous circulation.
Finally, the nerves of the breast come from anterior and lateral cutaneous branches
of the 4th through 6th intercostal nerves. 
The branches of the intercostal nerves go through the pectoral fascia covering
the pectoralis major in order to reach the overlying subcutaneous tissue and skin of
the breast. 
The branches of the intercostal nerves carry sensory fibers from the skin of the
breast and sympathetic fibers to the blood vessels in the breasts and smooth
muscle in the skin and nipple.

Summary
All right, as a quick recap. 
The breasts extend transversally from the lateral border of the sternum to the
midaxillary line and vertically from the 2nd through the 6th ribs. 
A small part of the breast might extend along the inferolateral edge of the pectoralis
major, forming the tail of Spence. 
The retromammary space is between the breast and the pectoral fascia, and allows
movement of the breast to the structures deep to it. 
The mammary glands are made up of 12 to 20 lobes, each of them containing
several small lobules, which further contain clusters of alveoli that
have mammary secretory epithelial cells. 
The alveoli, lobules and lobes are connected to ducts that join to form larger ducts
called lactiferous ducts, which drain the mammary
glands through lactiferous sinuses to the tip of the nipple.. 
The nipples are conical or cylindrical prominences in the centers of the areola and
have no fat, hair, or sweat glands. 
The areola are pigmented areas of skin surrounding the nipple. 
The stroma of the breast is composed of adipose tissue and fibrous connective
tissue which make up the bulk of the breast tissueand support the mammary
glands respectively. 
Arteries of the breast include the medial mammary branches, the lateral thoracic
artery, the thoraco-acromial arteries and posterior intercostal arteries. 
The venous drainage is mainly to the axillary vein, but there is some drainage to
the internal thoracic vein. 
Lymph from the lateral breast quadrants drains to the axillary lymph nodes, initially to
the anterior or pectoral nodes. 
The remaining lymph, especially from the medial breast quadrants, drains to the
parasternal lymph nodes or to the opposite breasts. 
Lymph from the inferior quadrants may pass deeply to abdominal lymph nodes. 
Lymph from the skin of the breast, with the exception of the nipple and areola, drains
into the ipsilateral axillary, inferior deep cervical, and infraclavicular lymph nodes and
also into the parasternal lymph nodes of both sides. 
The nerves innervating the breast come from anterior and lateral cutaneous
branches of the 4th through 6th intercostal nerves.