Ben Alcini

Cancer Biology: 2015

Cancer of the Central Nervous System

04/14/15

In today’s world, cancer is one of the most deadly diseases and is one of the

highest causes of death. Cancer in general, is the abnormal growth of cells into a tumor.

A tumor can either be benign or malignant, both dealing with the severity of the tumor

and the survival rate of the cancer. Cancers can arise from anywhere in the body and at

any age, but usually it is seen mostly in older patients. The reasoning behind the trend

seen with older people being diagnosed with cancer is that for the cancer to form,

events need to occur and mutations also need to take place. The timing for the

mutations to occur and the time between the mutations can be weeks to years, and

more often than not, the timing between the mutational events is years. In the most

recent years, cancer has become a more “household” name, and the more major

cancers or the more common cancers have become very well known to the general

public. These cancers include: lung cancer, colon cancer, breast cancer, and more. But

there are more than just the more frequent types of cancers, one being cancer of the

central nervous system (CNS).

In this type of cancer, tumors can form anywhere in the CNS with the majority of

them forming in the brain. Cancers of the CNS are rare and unlike other cancers, have

been known to affect a large number of children as well as adults. Cancer of the CNS is

a very serious type of cancer and not much is known about this cancer. Studies have

been done to determine more about this cancer in hopes to find a treatment, prevention,

and cause of the disease. A great amount of research is being done on cancer today, in

hopes to prevent or cure all the types of cancer. CNS cancer consists of different

cancers, all originating within the CNS of the body. The most common CNS cancer is

named Glioma, which can be broken down into 5 different types of cancer based on

what tissue they arise. The types of glioma are as follows: astrocytoma, ependymoma,

and oligodendroglioma. All of these types of glioma are slightly different from glioma in

the tissue they arise from and the events needed for their respected cancers to come

about. Astrocytoma is a cancer that arises from the astrocytes, the star-shaped cells

found in the brain; and ependymoma arises from ependymal cells that line the spinal

cord and ventricles of the brain. Like all cancers, CNS cancer has its share of known

causes, stages, and treatments. In most cancers, one can predict if whether or not the

cancer the patient has was inherited or sporadic based on the age and occupation of

the patient. Patients who are diagnosed with cancer at a young age and do not come in

contact with known causes, other than the unavoidable causes, the chances of that

person inheriting a mutation that started the cascade of events that lead to the cancer

are much higher. A cancer that is termed sporadic would be one found in older people

and takes years to develop due to the person needing the first mutation to start the

cascade. CNS cancer is no different, especially that of Glioma and ependymoma.

Glioma is the most common type of CNS cancer. Glioma affects both the brain

and the spinal cord, affecting 9 per 100,000 person- year with malignant tumors,

averaging adults 20 years and older (1). While this may seem like a small number over

the short time span of 1998 to 2002, the amount of malignant CNS tumors seen then

was increasingly high. Glioma is a cancer of the glial cells of the central nervous

system, which includes astrocytoma, ependymoma, and oligodendrogliomas. Glioma

accounts for approximately 80% of all malignant brain tumors and is one of the most

dangerous (1). Glioma can affect anyone at any time, but is mostly seen in either

children or adults and not between. There is a significant amount of children diagnosed

with CNS cancer each year, but not in the quantity that adults are diagnosed. Children

are able to develop the cancer because of the brains are in a state of developing rapidly

or that their parents passed on a mutation. The fact that children are being diagnosed

with this cancer is giving an emerging need for research on this cancer and possible

treatments.

In other studies performed by Ohgaki and Kleihues, they found that Caucasians

have a higher incidence rate of Glioma than both African American and Asian

populations (2). This can be due to the sample size of the different populations causing

the data to be skewed or it can be due to genetic differences in different geological

locations. Glioma, like other cancers, can be caused by mutations in the cell. Glioma

itself may or may not be inheritable but it is uncertain due to the fact that we still do not

know what exactly can cause the Glioma to occur in the first place. Due to the amount

of incidence in children, one can conclude that the cancer is inheritable and can occur

much faster through inheritance than through sporadic events. For the cancer to occur

sporadically, carcinogens must alter the cell in some way to allow for the cancer to form

and spread. As of today, there is only one known direct cause for Glioma, and that is

exposure to therapeutic dose or a high dose of radiation (1). The radiation causes an

alteration in the glial cells of the CNS and then the cascade takes place leading the

formation of the Glioma. Not much is known on how this causation occurs or why, or if

there is even any other exogenous causes to the cancer. In studies done on children

being treated for acute lymphoblastic leukemia via radiation have shown an increase

risk for Glioma, usually within a ten year span after the initial start of the treatment (2).

Here, Ohgaki and Kleihues conclude that the therapeutic radiation does play a major

role in the development and initiation of Glioma and possibly other CNS cancers.

A Glioma tumor can be classified into two different subclasses, a primary low

grade glioma and a secondary low grade glioma. With the primary glioma tumor, the

tumor is not known to have a precursor, whereas the secondary tumor does. (1). With

this separation, it is easier to help diagnose the patient and more definitive for the

treatment of the tumor. Secondary Glioma tumors can rise from a TP53 mutation in a

low-grade glioma, and is relatively consistent with all Gliomas. The role of the TP53

mutation in the formation or proliferation of the Glioma is still not clear, but it is clearly

seen along with EGFR amplifications (1, 2). These mutations, while the roles are not

clear, can be interpreted as significant based on the fact that in the majority of Glioma

patients these mutations have occurred in the secondary tumors.

Patients who have developed Glioma experience symptoms of cranial pressure

such as headaches, possible seizures, vision problems, changes in behaviors or habits,

or even nausea. All of these symptoms can be signs of a larger problem that could lead

to death if not treated right away. Since Glioma is a cancer of the CNS, it is extremely

hard to diagnose in the early stages because the symptoms do not appear till later in

the progression of the cancer. The methods of which are used to diagnose a patient

with Glioma is through the use of an MRI machine, CT scans, and a lumbar puncture

(3). The MRI and CT scans allow the doctors to be able to see the possible tumor and

its location and size. From there, they are more able to determine the classification of

the grade and potentially the type of glioma tumor. If the tumor is present on either

scan, a biopsy is performed in order to determine what exactly the tumor is and how to

proceed. Lumbar punctures are performed in order to determine whether or not the

cancer has metastasized, or spread to other parts of the CNS (3). CNS cancers will not

metastasize to outside of the CNS, and will be found in either the brain or the spinal

cord. If only one tumor is present on the MRI scan, then the tumor may have spread to

the spinal cord. A common problem with diagnosing a patient with Glioma is that just

based on the MRI alone, once cannot determine whether or not the tumor is Glioma

or just a brain abscess. In order to discern which the tumor is without having to do a

biopsy, tests called diffusion weight imaging can be performed to determine which the

tumor is (10). Based on this testing, brain abscesses can be differentiated from Glioma

based on the characteristic of brain abscesses having a reduced diffusion coefficient

while Glioma does not exhibit this characteristic (10). Being able to discern whether or

not the abnormal growth seen in the MRI is actually Glioma or not without having to take

a piece of the growth for examination is greatly needed and is quite helpful in the

diagnosis of Glioma. Had a patient just have a brain abscess and be treated for Glioma,

major consequences could follow and the patient would suffer to no reason.

Once the patient has been diagnosed and the examination of the tumor is

complete, the cancer will then be classified. Unlike other cancers that are classified into

stages, Glioma is classified based on many different aspects of the tumors. The Glioma

is first classified based on its cell type and location. As mentioned before, the type of

Glioma the cancer is, it is based on which type of cells they arise from such astrocytoma

is from the astrocytes of the brain (4). Instead of staging the tumor, Glioma is graded.

There are different levels of grading and are termed “WHO”, which is a grading system

based on the World Health Organization (11). There are four levels of which a Glioma

can be graded under the WHO system, WHO I, WHO II, and WHO III and WHO IV.

WHO I graded tumors are commonly found in the lower portion of the spinal cord and

not the brain, while WHO II tumors are commonly found in the upper spinal cord and no

the brain (5). This difference between the two grading levels shows the increase in the

intensity of the cancer from a cancer growing in the lower spine to a cancer that has

moved through the spine. WHO III is an anaplastic Glioma, and has metastasized

through the CNS either from the brain to the spine or throughout the brain (5) In general

WHO I tumors have a low potential for proliferation; WHO II is a tumor of low mitotic

activity. WHO III and IV are tumors that are more malignant, with WHO IV being

mitotically active and WHO III is not (11). The use of the WHO grading system is a way

for everyone internationally to understand what the tumor is and how far it has

progressed. This new system has cleared up the past confusion of how staging of a

Glioma should be completed, with it taking place in two different but key points in the

CNS.

Another method of which is used to classify the Glioma of a patient is classifying

the cancer as either low grade or high grade tumors and this deal with the size of the

tumors. Molecularly, Glioma tumors are broken down into two different pathways, a

primary and a secondary pathway (1). Primary pathways do not need a precursor for

the tumor to proliferate and the secondary tumor does. All of these classification tools

allow for the treatment of the cancer to be more effective and ideally shorter. By being

able to more accurately narrow down the type of Glioma a patient has, the more

chances there are for the patient to make a full recovery.

Like any other cancer, once a patient has been diagnosed with the cancer it is

best to start treatment right away. Treatment for cancer of the CNS is tricky and can be

quite risky in some cases, especially that of Glioma. Once diagnosed with Glioma and

the grading and stages have been determined, the usual course of action would be to

perform surgery to remove the cancer from the brain or spine if it had metastasized (6).

Surgery is the most efficient way to rid someone of Glioma, but it does come at a price.

In order to remove any cancer through means of surgery, a small amount of normal

tissue must be removed with it. In the case of Glioma, a small portion of the brain must

be removed in order to completely remove the tumor. This could cause serious damage

depending on the location of the tumor in the brain. Typically to treat the Glioma,

surgery is performed to remove as much of the tumor as possible with only removing

the minimum amount of normal tissue, leaving some of the Glioma tumor behind. Then

after the surgical removal of the tumor, the patient then must undergo radiation

treatments reduce and potentially kill the remaining pieces of the tumor (6). Due to the

nature of Glioma and that therapeutic radiation is a known cause for the formation of

Glioma, using radiation to treat the tumor can be perceived as counter-productive (1).

The known effect of the radiation on the tumor is not clear, and potentially causes the

tumor to increase in severity, in theory, though the surgical and radiation treatments

together work in treating the patient. In the worse scenario, if the surgery and radiation

treatments are not effective in treating the tumor or it the tumor returns, chemotherapy

is used as a last resort treatment (6). It is used as a last resort due to its effects on the

body and the nature of how it treats the patient. Using chemotherapy on Glioma could

potentially cause more damage than treatment.

Due to the nature of Glioma and the uneasiness of the current treatment options,

research is currently being done to look for more treatment options for Glioma and other

CNS cancers. As of today, due to the lack of knowledge of Glioma and its causes,

studies are being conducted in order to develop preventative measures or ways to

reduce the risk of developing Glioma. One method of treatment that is being studied

currently is the potential use of monoclonal antibodies (7). This new way of treatment

would allow for more specificity in the treatment of the cancerous cells in the brain. If we

were more able to only target the cancer cells and no the normal tissues, the likelihood

for the patient to survive without any more damage to the brain or spine would increase

significantly (7). Monoclonal antibodies would be able to target the cancer cell more

specifically than radiation or chemotherapy. The problem with the study of the use of the

monoclonal antibody is that without knowing more of the causes of Glioma or what is

mutated, the development of the antibody would take years to develop and in the world

of today the treatment would be inefficient. In the ways of prevention, research is being

conducted in the finding of a biomarker for Glioma (8). A biomarker is a substrate that

allows for the detection of a disease affecting the body in some way. By the use of the

biomarker, the potential of early detection of the Glioma is increased greatly, and

therefore the treatment of the tumor is also greatly increased. The current biomarkers

that are being researched on that could be used in the early detection of Glioma

include: MGMT, EGFR, VEGF, and PTEN (8). The use of these biomarkers would

greatly increase the survival and treatment rate of patients diagnosed with Glioma.

Future studies are being more focused on knowing more of the causes of the cancer,

and ways to be able to treat the cancer based on those causes. Like most others,

researchers of Glioma are focusing on better ways to more directly target and rid the

body of the cancer. The use of the monoclonal antibodies is a great step forward into

this new direction of treatment, especially with a cancer such as Glioma where you do

not want to damage or kill off any of the surrounding normal cells.

Other studies are currently being performed in hopes to find a treatment suitable

for Glioma. One method of treatment that is being researched on is based on the effects

of thermotherapy on Glioma tumors (9). In a study performed by Andreas and his team

studied the effects of thermotherapy on male Fisher rats. They used different kinds of

particles and frequency to determine which one, if any, would have an effect on the

tumor growth in the rats. What they found was that the thermotherapy resulted in a

antigrowth and antitumor effect in the rats (9). This new method for treating the tumor

cells would be efficient for Glioma in that it would not damage the surrounding normal

tissue and it would be less invasive that surgery. The use of thermotherapy would allow

for the treatment of Glioma, or any CNS cancer, to be more successful without the

damage to the normal tissue of the brain or spine. With the use of the biomarkers and

thermotherapy, early detection and treatment for Glioma would be more efficient and

allow for a decreased account of Glioma patients currently and in the future.

Overall, Glioma is a very complicated and still unknown cancer that greatly

affects many people throughout the world. Glioma is one the most common types of

CNS cancer, amounting to approximately 80% of the brain tumors seen in patients.

Glioma can be considered to be one of the more deadly cancers that it is not a

“household name such as lung cancer or breast cancer. Glioma and other CNS cancers

of the like are extremely hard to detect treat. With the limited knowledge of Glioma,

treating patients is not efficient some of the time. The use of surgery and radiation could

cause more harm than good for the patient that is diagnosed with Glioma, especially

with the only known environmental cause for Glioma is high-dose of radiation. The

process of staging and grading a tumor of Glioma is beneficial in that it create a more

accurate treatment method and routine, allowing for a more a greater chance of survival

for the patient. In the future, studies that look into the possible use of other means of

treatment and learning the causes of Glioma would increase the chance of survival and

for the prevention of Glioma from affecting more patients.

References

1.) Schwartzbaum, J., Fisher, J., & Aldape, K. (2006, January 1). Epidemiology and molecular pathology of glioma. Retrieved April 16, 2015, from http:// www.nature.com/nrneurol/journal/v2/n9/full/ncpneuro0289.html

2.) Ohgaki, H., & Kleihues, P. (2005, January 1). Result Filters. Retrieved April 16, 2015, from http:// www.ncbi.nlm.nih.gov/pubmed/15685439

3.) Ependymoma. (2012, January 1). Retrieved April 16, 2015, from http:// www.abta.org/secure/ependymoma-brochure.pdf

4.) Glioma. (n.d.). Retrieved April 16, 2015, from http:// www.abta.org/brain-tumor- information/types-of-tumors/glioma.html

5.) Villano, J. L., Parker, C. K., & Dolecek, T. A. (2013). Descriptive epidemiology of ependymal tumours in the United States. British Journal Of Cancer, 108(11), 2367-2371. doi:10.1038/bjc.2013.221

6.) http://www.abta.org/secure/ependymoma-brochure.pdf7.) Cheema, T., Wakimoto, H., Fecci, P., Ning, J., Kuroda, T., Jeyaretna, D., . . .

Rabkin, S. (2013). Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model. Proceedings of the National Academy of Sciences, 12006-12011. Retrieved April 16, 2015.

8.) McNamara, M. G., Sahebjam, S., & Mason, W. P. (2013). Emerging Biomarkers in Glioblastoma. Cancers, 5(3), 1103–1119. doi:10.3390/cancers5031103

9.) Jordan, A., Scholz, R., Maier-Hauff , K., Landeghem, F., Waldoefner, N., Teichgraeber, U., . . . Felix, R. (n.d.). The Effect Of Thermotherapy Using Magnetic Nanoparticles On Rat Malignant Glioma. Journal of Neuro-Oncology, 7-14 http://www.abta.org/brain-tumor-information/types-of-tumors/glioblastoma.html

10.) Lisak, R. (2009). International neurology a clinical approach. Chichester, UK: Wiley-Blackwell.

11.) Adult Brain Tumors Treatment. (2015, February 25). Retrieved April 16, 2015, fromhttp://www.cancer.gov/cancertopics/pdq/treatment/adultbrain/HealthProfessional/page2