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A
Simple Explanation of Gliomas: Growth Patterns and Imaging Studies
Patrick J. Kelly, MD, FACS
Professor and Chairman,
Department of Neurological Surgery,
New York University Medical Center,
New York, NY 10016
If
you took high school sophomore biology ... you can understand brain tumors.
The Brain
Water, water
everywhere....
The
brain floats in water, called spinal fluid, contained in a sac (the sub-arachnoid
space).
Most of the brain is water.
There's water on the inside in hollow cavities called the ventricles.
The brain substance is made up of trillions of cells which float in water
(the extracellular fluid).
Each cell is, in itself, mostly water within a cell membrane - the
intracellular fluid.
Cast of Characters
Do you
remember High School Biology? Your instructor brought in some swamp water and
you looked at it under a microscope. In a single drop of water were hundreds of
single celled animals; Amoebas, Parameciums, Euglenas, etc. They are called
Protozoan (Proto - first; zoa - life). Each single celled animal lives
independently of the other. Some could communicate with each other by sending
chemical messages. They produced their own energy. They moved around, ingested
food, avoided threats and excreted waste. They reproduced through a process
called mitosis - where one single cell animal becomes two single cell animals.
Every tissue in the body of more complex life forms (humans, for example)
is made up of millions and millions of single celled animals. But now they are
attached to each other and work together as an organism. The organism does all
of the things that primitive single celled animals do (move, breathe, find food,
excrete, avoid threats, reproduce, etc.). Some of the cells in the organism may
be better at some things than others. Some may be great at making the animal
move but not much good at ingesting food. This results in groups of cells being
organized into systems such as the gastrointestinal system, the muscular system,
and so forth. In a higher animal (like man) the single celled animals have
become highly specialized: some cells take over some of the basic
functions necessary to stay alive to support others which have learned some
fancy new tricks, like passing an electrical impulse, for example, as nerve or
muscle cells do.
Each cell in the brain is a "single celled animal" which has
been highly specialized in the process of evolution. Each performs specific
functions within the brain. Nerve cells pass electrical signals to each other.
But they are not very good at taking care of themselves. Nerve cells (neurons)
need other specialized cells to support them as they go about their specialized
functions (passing electrical signals). These specialized cells are called glial
cells.
There are several types of glial cells:
Astrocytes:
These
cells (cyte means cell) are star shaped (thus the name astro..) They have
several functions, but their most important function is the following:
Astrocytes draw nutrients from blood vessels and pass it to neurons.
Neurons require and consume a tremendous amount of food (glucose) from which
they produce energy. And like people who eat and digest a huge meal, they must
go to the bathroom: neurons must excrete the by-products of digestion. (They
can't excrete this nasty stuff into the water bath they are floating in - it
would quickly poison other cells and themselves, too.) Astrocytes, therefore,
also act as a sewage system. They collect the by-products of metabolism and dump
it into the blood vessels where it is carried away.
Astrocytes and neurons are like husband and wife. Their relationship is
like a marriage: the spouse (astrocyte) feeds, cleans up after and does the
laundry of the wage earner (neuron).
Neurons "work" by making electrical signals that pass down
extensions of their cell bodies (axons) to their feet (terminal boutons). There
the electrical pulse causes the release of a chemical (neurotransmitter). This
chemical molecule floats in the water (extracellular fluid) until it hits the
side of another neuron. Here it causes an electrical disturbance. The electrical
disturbance causes that neuron to generate an electrical pulse. This is then
passed down its axon, and so on. Axons can be very long - in man some up to 4
feet in length! The electrical signals (called action potentials) pass down the
cell body of a neuron like the ripples in the water of a smooth stream after
you've thrown a stone into it. This is not very fast. If the neuron had some
insulation around the axon the electrical pulse could jump from one region of
the cell body to another. This brings us to the second glial cell type: the
oligodendroglial cell.
Oligodendrocyte:
These
cells form the insulating material called myelin. The oligodendroglial
cell (same as oligodendrocyte) wraps itself around the axon of a neuron and then
makes layer upon layer of myelin. This insulates the axon - similar to the
rubber or plastic insulation you have around the copper wires which connect
electrical appliances to wall power. Electrical signals from the neuron's cell
body, instead of passing down the entire length of the axon, can now jump
between small uninsulated regions along the axon called nodes. These nodes are
where one the myelin produced by one oligodendrocyte ends and the myelin
produced by another oligodendrocyte begins. Nerve electrical signal conduction
jumping from node to node is much faster than simple transmission of a wave down
the axon. The oligodendrocytes make this rapid signal transmission possible.
The general arrangement of these cells is shown in figure 1:
Figure
1: Cartoon showing
two neurons (with cell bodies and axons), two astrocytes, a capillary blood
vessel and oligodendrocytes. The oligodendrocytes wrap around the axons of the
neurons. Note that the astrocytes have long processes which extend to and wrap
around the blood vessel and other processes which extend to the neuron. All of
these cells are suspended in water - the extracellular fluid.
Ependymal cells:
The
center of the brain is hollow. These hollow cavities (called ventricles) contain
water (ventricular fluid). Ventricular fluid water is not exactly the same as
the water in the extracellular space (which has neurotransmitters and other
stuff floating around in it). Like fresh water and sea water. Something must,
therefore, line the walls of the ventricles to keep ventricular fluid and
extracellular fluid from mixing. This lining is called the ependyma. The
ependyma is really a continuous sheet of cells standing shoulder to shoulder to
form a living wall. These cells are called ependymal cells.
Microglial cells:
These
cells are a cross between a policeman and a cleaning lady. Microglial cells
attack and remove foreign substances - like bacteria, for example. When other
cells die due to an injury, microglial cells ("gitter cells") clean up
the mess. In many ways they are like white blood cells in the circulatory
system.
Embryonic Development:
How
these cells get to be the way they are...
It is important to realize that all of these different cells develop and
become specialized as the brain grows between conception and the birth of an
infant. The first cells to form after conception are very primitive cells. They
can, in theory, become anything; an astrocyte, a neuron, a cell lining your
stomach wall. However, they inherit a road map - the internal genetic code which
will determine, in part, what they will become.
Early in development, (like geese heading South for the winter) cells
align themselves in three basic layers: endoderm (which becomes, among
other things, gut), mesoderm (which becomes, among other things, muscle
and blood vessels) and ectoderm(which becomes, among other things, skin
and the nervous system). In the nervous system some of these primitive
ectodermal cells become neurons, some astrocytes and some oligodendroglial cells
and some wait around to become whatever is needed. Why?
Well, first, there is the inherited genetic code which determines how
many times the cell will undergo mitosis (reproduce) and how to look and how to
behave. Second, a cell can become what is required in it's own environment. From
simple single celled protozoaic animals up to specialized human brain neurons,
cells can actually "talk" to each other. They do so by sending
chemical messages to each others. These are called cytokines. Some of these are
growth factors, others tell a cell to "move over", others tell a cell
to make something. A developing neuron may send out a chemical message (growth
factor) saying: "hey, I need an astrocyte to keep me company" and a
primitive ectodermal cell nearby receives this message, becomes an astrocyte and
sends an extension of its cell body (called a process) to the lonely neuron.
An astrocyte needs nourishment for itself and it needs to pass
nourishment to the neuron. It grows toward a group of endothelial cells (the
cells that line blood vessels). The endothelial cells or blood cells within them
send out chemical messages (growth factors) which stimulate the astrocyte to
send a process toward them. The astrocytic process then wraps its foot around
the capillary as if to stop it from sending out these stupid messages.
The nervous system (and any other tissue in any animal organ system) is a
complex ecosystem where all cells depend upon each other, support each other and
make the "mission" of the organ system possible. Specialized cells
that cannot be supported, are too "different" or have no function in
this developing ecosystem are removed in a variety of ways. Some, however, never
become specialized, stick around as freeloaders and may have something to do
with the development of certain tumors later in life.
Now let's talk about
Glial Tumors
The
"cast of characters" (cell types) in the fully developed central
nervous system (brain and spinal cord) is small: we have neurons, astrocytes,
oligodendroglial cells, microglial cells, ependymal cells, blood vessel cells
(endothelial cells) and a few remaining primitive (neuro)ectodermal cells. Any
of these cells can become a tumor. Here they are:
Astrocytes
can become astrocytomas.
Oligodendrocytes
can become Oligodendrogliomas.
Microglial
cells can become a
Microglioma which is now called a Primary nervous system lymphoma.
Primitive
ectodermal cells
can become Primitive Neuroectodermal Tumors PNETs such as a Medulloblastoma.
Ependymal
cells can become Ependymomas.
These are the basic cellular subtypes. However, some tumors can have two
or even three different cell types. These so-called mixed gliomas can have cells
which were derived from astrocytes and cells which were derived from
oligodendroglial cells combined. They are called "oligoastrocytomas".
Some rare tumors have primitive nerve cells within the tumor as well as
astrocytes and/or oligodendroglial cells. These are gangliogliomas.
How are tumor cells
different?
Consider
a tumor as a mass of abnormal cells (any type). What's abnormal about any of
these cells? Well, first they are performing no useful functions important to
the mission of the organ system in which they reside. Nevertheless, they are
gobbling up food and using oxygen needed by normal cells and excreting their
metabolic by-products into the extracellular fluid. Second, they have an
abnormal rate of mitosis which is higher than their "normal" siblings.
Third, some of them are capable of moving from one place to another (in contrast
to normal cells - a normal astrocyte tethered to blood vessel and neuron or
oligodendroglial cell wrapped around a neuron -which cannot move). Fourth, they
seem to be able to avoid detection from the internal policemen (immunologic
system) which ordinarily would identify and kill these creeps.
Growth Patterns
Glial
tumors grow in two basic ways: By tumor cell invasion into normal tissue
and by volume expansion of a mass. Many glial tumors start by isolated
tumor cell invasion and then develop into a mass as described below and in the
following set of images:
The first thing that happens is that a tumor cell has to evolve from a
normal cell. There are many theories as to why and how this happens.
Here's
a simple theory for the transformation of normal cell into tumor cell by
mutation...
This
theory may not be 100% correct, but it "works":
The transformation of normal cell into tumor cell could be due to a
simple process of cellular mutation. Cellular mutation has taken place in animal
cells for millions of years. Simply put, mutation is an accident which occurs
during mitosis and causes the offspring of that mitosis to be different from the
parent. In general, mutation is a good thing because it allowed single celled
animals to develop new capabilities and made new types of animals. (If it were
not for mutation, you and I would still be swimming around in some ocean as
single celled animals!)
Human cells stll undergo mutations. One in every ten million cells in
humans is a mutant cell. Our bodies turn over that many cells a couple of times
a day. At that rate it is a miracle that we aren't all walking around with
tumors. Nonetheless, only a small percentage of these cells are actually capable
of living. Most of the ones that can survive are killed by our immunologic
system. However, one cell may evolve which can survive and "fool" the
immunologic system. This, then, starts the series of events from which a glioma
evolves.
The following will illustrate the events for an astrocytoma.
Nevertheless, the same scenario is probably true for other types of glial
tumors: oligodendrogliomas, mixed gliomas, some PNETs, etc.
Figure
2: Transformed
astrocyte pulls in its processes and detaches itself from neuron and blood
vessel.
This cell is different. Note in Figure 2 that something has happened to
the second astrocyte: it has pulled in its processes and is no longer attached
to blood vessel or neuron. It is now capable of mitosis (the process by which
one cell becomes 2 cells) and it is capable of movement.
Figure
3: Tumor cell
undergoes mitosis where one cell becomes 2 cells. It is the reproductive method
of all single celled animals and all cells within organ systems of every species
in the animal kingdom.
The new cell undergoes mitosis to form others like itself. How
often will the cell undergo mitoses?
This is a critical question. The rate at which cells undergo mitosis
separate:
"Low
grade" tumors which have a very low mitotic rate and a better prognosis
from
"High
grade" tumors which have a high mitotic rate and a poor prognosis.
Figure
4: Two tumor cells
following mitosis. Each are completely independent and can survive without the
assistance of each other and the normal cells in their environment.
The tumor cell is now no different than primitive single celled animals
that live in water anywhere. In this case, the single celled animal (the tumor
cell) lives in the water is the extracellular fluid of the patient's brain.
The new (tumor) cells have abilities to undergo mitosis and to move from
one place to another. Here we see some variation between different tumor types:
some tumor cells can't move well at all. They just undergo an occasional mitosis
and new cells keep piling up on each other. The tumor simply grows as a solid
mass as seen in Juvenile Pilocytic Astrocytomas and some other (rare)
glial tumor types.
Other tumor cells can move very well. These cells disperse themselves
through the extracellular fluid and do not, at this stage of tumor development,
grow as a solid mass. This pattern is seen much more commonly in glial tumors (fibrillary
astrocytomas, oligodendrogliomas, mixed gliomas). This is the reason why we
have such a hard time treating them.
Let's now return to our
tumor cells..as the glioma develops:
The new
cell can live independently. It can generate its own energy and excretes its
metabolic waste into the extracellular fluid as shown in Figure 5.
Figure
5: Tumor cells are
capable of movement as well as mitosis but probably not at the same time. They
have to stop moving in order to reproduce.
Tumor cells require energy-like all cells everywhere. Like the primitive
single celled animals that they are, they extract glucose and other nutrients
and oxygen from the extracellular fluid water. Their digestion produces
by-products which are excreted into the extracellular fluid as depicted in
Figure 6.
Figure
6: Mitoses have
produced more tumor cells. Cell movement has allowed tumor cells to spread to
new (and less polluted) areas.
The added molecules excreted into the confined extracellular fluid space
changes the osmotic gradient. Osmosis is a law which determines the amount
concentration of fluid across a membrane. In this case the membrane is the blood
vessel walls. A higher concentration of stuff in the water tends to draw fluid
from areas of lower concentration of stuff to areas of higher concentration in
an attempt to have the distribution of water and "stuff (proteins,
molecules and solute)" equal. The principle is illustrated in Figure 7.
Figure
7: Principle of
osmotic flow. A higher concentration of molecules outside of the blood vessel
(in the extracellular fluid) tends to draw water out of the blood vessel into
the extracellular fluid.
The increase in extracellular water is called "edema" or
"swelling". It usually is confined to areas having a concentration of
isolated tumor cells which are polluting the extracellular fluid space. This is
important to Doctors because the "edema" is now apparent on computed
tomography (CT scanning) and Magnetic Resonance Imaging (MRI) as shown in Figure
8.
Figure
8: CT scan (left),
T1 MRI (middle) and T2 MRI (right) in a patient with a low grade glioma manifest
by isolated tumor cells which have invaded a large area of parenchyma and caused
edema which is evident deep in the brain on the patient's right side (CT and MRI
images are flipped so that the patient's left is on the right side of the image
and the patient's right is on the left side of the image).
In the case shown in figure 8 the "tumor" is composed only of
isolated tumor cells within intact and functioning brain tissue. It was biopsied
by a stereotactic probe and called an oligodendroglioma. The scenario described
above and illustrated for astrocytes is also true for oligodendrogliomas. In the
case of an oligodendroglioma the cell no longer produces myelin, detaches itself
from the neuron and lives as a single celled animal as we have been describing.
Most glial neoplasms up to this stage are the same regardless of the cell type
of origin.
So what's going on with the patient at this stage? The tumor cells have
created a metabolic abnormality within a region of intact brain tissue. There's
too much water and there's too much "junk" in the extracellular fluid.
The neurons don't like it: not only is water getting extracted from the blood
vessels to balance the water concentration in the extracellular fluid, water is
also being sucked out of their cells (the intracellular fluid) which changes the
concentrations of electrolytes necessary for them to maintain their resting
membrane voltage. The neurons become irritable. They begin to have spontaneous
and erratic electrical discharges. This manifests itself clinically as seizures.
Can a surgeon remove all of this bad tissue shown on the CT and MRI scan?
Certainly, he or she can. With computer-assisted volumetric stereotaxis this is
possible. However, remember that the brain tissue, the neurons, astrocytes,
oligodendroglial cells, etc. are still alive and functioning. Removing the
"tumor" at this stage is, in fact, removing functioning brain tissue
and a neurological deficit (paralysis, speech problems, visual difficulties,
etc.) will result if the process is located in important brain tissue. However,
when this process is located in an expendable region of the brain such as the
frontal or temporal lobe, a "tumor" at this stage can be removed with
the understanding that functioning brain tissue is being removed in the process.
What happens next?...
Up to
this point we have concentrated on isolated tumor cells that are moving, causing
pollution of the extracellular fluid and making a general pest of themselves by
causing seizures. Anticonvulsant medications such as Dilantin, Phenobarbital,
Tegretol, etc. usually control the seizures. What happens next? Well sometimes
the tumor cells have a very low mitotic rate -perhaps only 1 or 2 percent of
them may be capable of undergoing mitosis at any time. These "tumors"
will "grow" only very slowly as the mobile but mitotically inactive
cells move slowly into adjacent areas of healthy brain tissue. Patients with
tumors such as this can lead healthy productive lives for many (sometimes up to
30) years. In addition, there is a process called apoptosis which is a
process by which cells die. If the mitotic rate of the tumor is equal to the
apoptotic rate, no new tumor cells will be generated and the tumor will not grow
or do anything except cause seizures.
Unfortuately, many patients with glial tumors have tumors with a mitotic
rate higher than the rate of cell death. The number of tumor cells, therefore,
increases. Tumor cells that have a higher rate of mitosis tend not to move. The
production of new cells creates a local population explosion and overcrowding.
New cells are produced and stay in one spot. They all want to survive. They draw
more and more oxygen and nutrient from the extracellular fluid which is
deposited there by the blood vessels.
But there's not enough oxygen and nutrient in the extracellular fluid to
support all the tumor cells. In addition, the oxygen and nutrient is secondarily
being depleted from the blood vessels and this starts to starve the astrocytes,
neurons and oligodendroglial cells. Endothelial growth factors (cytokines
...chemical messengers) get secreted by the normal and tumor cells. These
cytokines tell the blood vessel endothelial cells to get busy, produce more
endothelial cells, make more blood vessels and have them grow into the mass of
tumor cells which are now falling over each other and eating up everything in
sight.
Figure
9: Mitotically
active tumor cells have not travelled away but have stayed in the same location
now require more nourishment than available only through the extracellular
fluid. Cytokines (such as the so-called Tumor Angiogenesis Factor) are produced
by the tumor cells and probably normal cells also. This results in mitosis
(reproduction) of the blood vessel endothelial cells which form new blood
vessels to supply the tumor.
The added nourishment and oxygen brought by the newly formed blood
vessels allows three things to happen:
1.
Tumor cells are able to speed up the energy-intensive process of mitosis.
2.
Newly formed blood vessels are different than normal brain blood vessels. Newly
formed blood vessels do not have the cuffing of normal astrocyte foot processes
which supply what is known as the Blood Brain Barrier.
3.
Newly formed blood vessels are "leaky". They let in all sorts of stuff
which is normally kept out of the brain: proteins, peptide factors like Tumor
Necrosis Factor, white blood cells, macrophages and lymphocytes. And large
molecule chemotherapeutic agents.
We now have a solid mass of tumor supplied with blood vessels as shown in
Figure 10.
Figure
10: A solid mass
of tumor cells lumped together, growing outward as more cells are added to the
mass by mitosis. Newly formed blood vessels supply the mass with everything the
cells need to survive and grow. The nerve cells, astrocytes and oligodengroglial
cells are now being starved and will die. This is when the patient will now
show a neurological deficit.
As mentioned above in normal brain blood vessels capillary endothelial
cells are surrounded by the foot processes of astrocytes. These form a
"tight junction" which exclude everything but the smallest molecules.
The newly formed tumor blood vessels leak. Large molecules which are normally
excluded from the extracellular fluid of the brain where the tight junctions are
intact (Blood Brain Barrier), can now pass from the blood stream into the brain
extracellular space. Intravenous contrast agents like Gadolinium given during
MRI examinations are normally excluded from normal brain as well as brain tissue
infiltrated by isolated tumor cells (see figure 8 - Note that there is no
contrast enhancement. The infiltrating "tumor" which has not yet
formed a mass of solid tumor tissue and, therefore, no new blood vessels which
would allow the contrast agent to leak into the extracellular space).
A mass of solid tumor tissue, as shown in figure 10, is supplied by
abnormal newly formed leaky blood vessels. Contrast agents given intravenously
during CT and MRI examinations pass through these leaky blood vessels and
accumulate in the tumor tissue mass. This results in the "contrast
enhancing mass lesion" usually (but not always ) associated with a
malignant glial tumor as shown in Figure 11.
Figure
11: A CT scan
showing a contrast enhancing left thalamic tumor (The white spherical mass).
This is composed of a solid mass of tumor cells which have replaced the
underlying brain tissue. Newly formed blood vessels within the tumor tissue mass
allow the contrast agent to pass into the tumor mass from the blood stream. Note
the black rim around the white mass. This is "edema" or swelling of
the surrounding brain due to tumor cell infiltration of the surrounding intact
brain tissue.
The normal brain cells within this contrast enhancing tumor tissue mass
are dead. The tumor mass will continue to grow by volume expansion and by
forming new tumor tissue which replaces the brain tissue at the periphery of the
contrast enhancing mass. The brain tissue around the mass is infiltrated by
isolated tumor cells just as we have seen in figures 4, 5 and 6. A surgeon could
remove this contrast enhancing mass of solid tumor tissue. There are no normal
cells within it. There should be no neurological deficit following the surgery.
However, the tumor would come back. Why?
The isolated tumor cells which have infiltrated the periphery (the
surrounding black area) on the CT scan in figure 11) would continue to undergo
mitoses and would continue to add more cells which would then stimulate the
formation of more newly formed blood vessels.
Highly malignant tumors (those with a high mitotic rate) grow so fast
that they outgrow their blood supply. The cells in the center of the mass die.
Also Tumor Necrosis Factor secreted by macrophages which enter the tumor mass
through leaky newly formed blood vessels, kills tumor cells also. This process
is call necrosis (necro.. meaning dead). The general configuration of
the tumor at this stage is shown in Figure 12.
Figure
12: The tumor mass
has killed the background neurons and other normal cells. It has outpaced its
blood supply and the center of the tumor has undergone necrosis. This picture
does not show the fact that this tumor mass is surrounded by isolated tumor
cells which can extend a great distance (up to 3 inches - 7 cms.) into the
surrounding functional brain tissue.
On CT and MR imaging the necrotic (dead) portion of a tumor tissue mass
does not accept intravenous contrast. It appears as a "black hole"
within the white mass defined by the contrast enhancement as shown in Figure 13.
Figure
13: Contrast
enhanced CT scan (left), T1 MRI (middle) and T2 MRI (right) in a patient with a
high grade glioma (Glioblastoma). Note the black area of necrosis within the
contrast enhancing (white) mass. Isolated tumor cells extend into the normal
brain tissue around this lesion.
The Natural History of
Gliomas...what is going to happen?
We now
understand gliomas at a cellular level. Of course, there are many, many
unanswered questions of why tumor cells develop in the first place and why they
do what they do. Answers to these scientific questions are being sought in
research laboratories around the world. Nevertheless, patients with gliomas have
more practical and timely questions: they want to know the future of an
individual tumor. They want to know what it will do to them if it is not treated
or if treatment is unsuccessful.
In order to answer these important questions, we must make several
assumptions based on over 100 years of scientific obsevation of patients with
gliomas:
1.
Tumors grow by adding new cells by the process of mitosis. Not all cells in a
tumor are capable of mitosis at any time. There is a pre-set "cell
cycle". However, even a tumor with only 2% of the cells capable of
undergoing mitosis will eventually add more cells and "grow".
2. A
larger tumor grows faster than a smaller tumor. Why? It's simple. A larger tumor
has more cells than a smaller tumor. If both have the same rate of mitosis (say,
for example, 2 % of the cells of each tumor are capable of undergoing mitosis) a
large tumor with 100 million cells will contain 2 million mitotically active
cells, while a small tumor with, say, 1 million cells will contain only 20
thousand cells.
3.
Some glioma cells that have undergone mitosis will contimue to undergo mitoses
in the future. It is therefore unlikely that a gliomas will stop growing and
they won't "go away".
4.
Some tumor cells will die through apoptosis (a program of cell death), some
will be killed by the immune system and others may mutate into cells which
cannot survive in the envirmonment. Tumor cell gain = tumor production (mitoses)
- tumor cell loss.
5. Some
tumor cells increase the rate at which they undergo mitosis in each suceeding
tumor cell generation. For example, the "offspring" of a cell which
divides every two months may undergo mitosis every month. Their offspring may
divide every two weeks...ans so on....
6.
Tumor
cells cannot move and undergo mitosis at the same time. When they stop moving,
some start dividing (undergoing mitosis).
7.
Tumor cells which cannot move and undergo mitosis form a solid tumor tissue
mass.
8.
Masses of tumor cells which have formed tumor tissue find space only by pushing
brrain tissue aside (which is hard to do since everything in the brain is
interconnected) or by destroying and replacing the normal cells of the brain
substance.
9.
Destruction of brain tissue in important areas of the brain leads to
neurological deficits; such as sensory loss, meakness, paralysis. As the tumor
grows into important brain areas (and it will) all patients will potentially
have a neurological deficit which will get worse as the tumor grows.
10."Host
factors" - the body's ability to fight disease- varies considerably from
person to person.
11.
Patients with neurologic deficits have a difficult time keeping other organ
systems "healthy" . They cannot maintain their ability to fight the
tumor immunologically. The tumor grows faster. They also have a difficult time
fighting infections. They get pneumonia and urinary tract infections. Like any
"cancer" patient, they don't really feel like eating. They lose
weight. They become dehydrated. Their blood becomes "thicker" and can
clot in their veins. Since the legs are the part of the body most affected by
gravity, blood clotting in the legs -thrombophlebitis- occurs. These clots can
break loose and go to the lungs - pulmonary embolisation. This, in itself, can
be fatal.
12.
The brain is encased in a closed box - the skull - which normally has
room for brain tissue, blood (in the blood vessels) and water (intracellular,
extracellular, intraventricular and in the subarachnoid spaces). If a tumor mass
plus edema is added to these contents something has to give. Pressure inside the
skull (intracranial pressure) goes up. The patient at this stage will complain
of headaches.
At
first, water in the extracellular spaces is redistributed in order to normalize
intracranial pressure. This buys some time. Next, the contents within the skull
start to shift to make room for the expanding tumor. This traps important blood
vessels and results in loss of blood supply to "normal" regions of the
brain. Eventually, the deeper areas of the brain which maintain consciousness
are compressed. The patient lapses into a coma. While in that coma, the patient
may die of pneumonia or sepsis (infection in the blood). If the nursing care is
good and the patient continues to survive the tumor continues to grow.
Eventually, parts of the brain are pushed out through a hole at the bottom of
the skull (called the foramen Magnum). This compresses the lower brain stem
which contains centers which control the heart and breathing.
Grading of Gliomas
Patients
having gliomas want to know whether their tumor can be treated and if so cured.
If it can't be cured; they want to know how long they have to live without
treatment and with treatment? They want to know how long they will remain
functional: for how long will they be able to work and if they can't work, how
long will they be independent and able to take care of themselves. This is
basically what we (physicians) mean by the Prognosis.
The prognosis in glial tumors depends heavily on tumor cell type and on
tumor grade. It also depends on:
-
The age of the patient (young patients do better than old
patients).
- The location of the tumor (tumors that can be completely removed
because they lie in unimportant brain tissue will do better than those with
tumors in neurologically important areas.).
-
The neurological condition of the patient. Patients who are
neurologically normal do better than those with a deficit (e.g. paralysis of one
side).
- The response of that particular tumor to therapy. Surgery, Radiation and
Chemotherapy.
Tumor Grading
Grading
is more of an art than a science and there is a lot of variability among
neuropathologists. Some pathologists use a numerical grading system:
Tumors are graded from 1 to 4 where 1 is the slowest growing (most benign) and 4
is the fastest growing (most malignant) as described in the piece on Astrocytomas.
Others use a three-tiered grading system: low grade (benign, slow
growing), anaplastic (malignant potential) and High Grade - Glioblastoma
(malignant).
Grading is dependent on what the pathologist sees under the microscope:
Evidence of Mitosis:
Mitotic
figures indicate that the tumor cells are growing. The number of cells
discovered in the process of mitosis as a proportion of the total number of
tumor cells present is related to prognosis. The higher the percentage of
mitotic cells, the more malignant the tumor, the higher the grade and the poorer
the prognosis.
Abnormal (atypical)
cells:
Tumor
cells do not look like normal cells. In general, the funnier they look, the
worse they are. The center structure in the cell body, the nucleus, is of
particular interest. This is the structure that carries the genetic material. If
this is very abnormal, so are the cells that will be derived from mitoses.
Abnormal Blood Vessels:
As
explained above, tumor cells being produced rapidly induce abnormal blood
vessels. Their presence indicates malignancy in some (but not all) tumors.
Necrosis:
Necrosis
usually indicates that a tumor has grown faster than its blood supply. A fast
growing tumor is a malignant tumor. The presence of necrosis is helpful only in
newly diagnosed tumors. It has less value in patients that have had radiation or
chemotherapy.
Tumor cell types
Tumor
cell types are also important in determining prognosis. Some cell types are
good, some are bad and others are in the middle. We defined the cell types
above:
Astrocytoma
Oligodendroglioma
Oligoastrocytoma (mixed glioma)
PNETs
Ependymoma
Ganglioglioma
Dysembryoplastic Neuroepithelial Tumors (DNET)
Prognosis and Tumor Cell
Type
Let's
talk about the best tumors to have and then progress to the worst. The best
tumors to have are those that do not grow at all, those that grow slowly, those
that grow as a solid mass of tumor tissue which pushes the brain tissue aside
and those that can be totally removed at surgery.
Gangliogliomas and Dysembryoplastic Neuroepithelial Tumors (DNETs) do not
grow or grow very slowly and can be removed (and cured ) by surgery. They are
therefore good to have, if you are going to have a tumor at all.
Juvenile Pilocytic Astrocytomas (JPAs) grow as a solid tumor tissue mass
and only rarely infiltrate the surrounding brain tissue. They grow very slowly.
Many can be completely removed at surgery and can be cured. They are good to
have.
Oligodendrogliomas are a little more difficult. In children many grow as
a solid tumor tissue mass. They can be cured by surgery. In young and middle
aged adults, they frequently present with seizures and as a zone of infiltrated
brain tissue. Removing the tumor means removing sick (tumor cell infiltrated)
brain tissue. This can be done if the brain tissue is not important for
neurologic function. This is determined by preoperative non-invasive mapping such
as Magnetoencephalography
(MEG), PET or
functional MRI or intraoperative mapping procedures. If the entire tumor
(infiltrated parenchyma plus solid tumor tissue) is removed in a volumetric
fashion the prognosis is excellent with survivals of 10 to 15 years being noted.
Malignant oligodendrogliomas (with high mitotic rates and necrosis) can, and
usually do, recur.
Astrocytomas are the worst cell type in comparison to other tumor cell
types . They grow faster than oligodendrogliomas. They tend to develop malignant
changes and become progressively more malignant. They are not cured by any
therapy yet tried. For more information on astrocytomas go to
http://mcns10.med.nyu.edu/tumors/astro.html.
A mixture of oligodendroglioma and astrocytoma is a associated with a
prognosis somewhere in between these two pure tumor types. Finding astrocytic
tumor cells within an oligodendroglial tumor confers a poorer prognosis. Many
will recommend radiation and/or chemotherapy for these mixed tumors following
even complete surgical removal.
Summary: what does all of
this mean?
In
summary, a glial tumor has two parts: a solid tumor tissue mass of tumor
cells bunched together (where the normal brain cells have already been destroyed
or pushed away) and infiltrating isolated tumor cells which reside in a
surrounding zone of “sick” brain tissue
(“sick” because this brain tissue is infested with these
moving and reproducing single celled animals called tumor cells). The tumor
tissue mass can be completely removed at surgery- especially if a
computer-assisted volumetric stereotactic method is
used. Getting rid of the isolated tumor cells represents the real challenge: one
cannot surgically remove them-you remove the normal brain cells with them.
Radiation therapy may damage them, but the normal cells are being radiated also.
Finally, these cells reside in regions with an intact blood-brain barrier (remember
that “leaky” blood vessels are found only in regions with
solid tumor tissue with newly formed blood vessels). Most chemotherapeutic
agents do not pass the blood-brain barrier.
Treatment
What is the benefit and risk of the various treatments?
What are the side effects?
© All
rights reserved by NYU Dept.of Neurosurgery
Source: http://mcsn10.med.nyu.edu/intro/brain.tumor.primer.html
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