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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...
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:
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.
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