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Neuro-Oncology
*(Fig 1. Optic Nerve Glioma)
This section that FLENI has created is devoted to the comprehensive attention of adults and paediatrics patients with tumors of the Nervous System, as well as the neurological complications of tumors located at other sites.
Tumours of the Central (CNS) and Peripheral Nervous System (PNS) make up a heterogeneous group of diseases that vary from benign, low-grade malignancy and even malignant lesions. In some cases, if these lesions are not treated quickly, they can cause the patient's death in a short time.
Each one of these tumours have their own clinical radiographic and biological features that will largely lead toward the medical management of this pathology. In Argentina, according to the Health Statistics and Information Office, only the number of deaths due to primary malignant tumours of the CNS is available for the year 2000. There were 890 deaths (480 males, 410 females), approximately 10% of the total corresponding to the paediatric population (1-19 years) and 70% to adults patients (50 to 79 years). If we resort to the world literature, we find that primary tumors of the brain in adults, are relatively rare compared with lung, breast, colon or prostate cancer. However, we know that cerebral and spinal cord tumors are among the 10 causes of death related with cancer in this population. In the paediatric group, the incidence and statistics are different, since tumors of the brain are found within the first cause considering solid tumors (e.g., gliomas, medulloblastomas) and they rank in the second place after leukemia (cancer of blood cells), within the general causes of cancer in children.
In the USA, the annual incidence of primary brain tumors is 12 for each 100,000 inhabitants, half of which are malignant. From these figures, we learn that approximately 13,000 people die every year from tumours in the CNS in this country. In general, the neoplasias of glial cells in the brain are those more commonly seen in adults, and they include low-grade tumours, as infiltrating astrocytomas, oligodendrogliomas and oligo-astrocytomas (mixed tumours). Tumours of intermediate grade include anaplasic astrocytomas. anaplastic oligodendrogliomas and anaplastic oligo-astrocytomas. The glial tumor with the greatest grade of malignancy is the glioblastoma multiforme. Paediatric tumours include the pilocytic astrocytoma, primitive neuroectodermic tumors (PNET´s) as the medulloblastoma, the ependymoma and a variety of less frequent tumours, as the germinomas and the atypical teratoid/rhabdoid tumors (ATT/R) of the central nervous system.
The localization of such tumors presents an important challenge for the neurosurgeon who will attempt to remove them and thus achieve an appropriate diagnosis with the invaluable collaboration of the neuro-pathological team, a critical group in every neuro-oncology group that will contribute with a correct histological report. A small group of tumours presents typical clinical, radiological or laboratory features so that a biopsy or surgical resection could not be suitable, particularly if the tumor is located in critical areas of the brain, where the risk of such procedures is greater that the potential benefit of obtaining material to study. However, the main objective of neuro-oncology is to remove most of the tumour, insofar as this ideal is safe for the patient. Fortunately, with the advent of new tools for computer-assisted surgical navigation (Neuro-navigator), as well as functional neuro-images (Functional Magnetic Resonance Imaging), today these objectives may be achieved with a millimetre-like precision impossible in the past. Once the diagnosis is obtained, the treatment instituted by the neuro-oncologist will consist of a specific therapy for each type of tumor. Some of them are surgically "curable", but the great majority will require some other type of therapeutic approach that differs from a range of simple, but thorough surveillance, up to
radiotherapy, chemotherapy, a properly protocolized experimental treatment, or even, successive surgeries.
The treatment in the paediatric population with cerebral tumours can differ substantially from the therapeutic options in the adults. Babies, infants, adolescents and even young adults cannot tolerate the long term risks that radiotherapy may cause, and many efforts of clinical research in this area are based on the use of chemotherapy use that, though not free of collateral effects, in their great majority these will be temporary.
The evolution of CNS tumours is influenced by a considerable quantity of factors, some of which have already been enumerated, as age, the histological tumor type, molecular biology and intrinsic genetic factors of the tumor, the clinico-neurological condition of the patient, the localization of the tumor, the volume of the tumour and the magnitude of surgical resection carried out, as well as the coadjuvant (complementary) treatment practiced. All these factors will converge to outline a prognostic profile of the illness that will guide the neuro-oncologist to be able to transmit a considered opinion to the patient him/herself, to the relatives, colleagues and to the whole health equipment involved in the attendance and care of this patient.
* 1. How is a Neuro-oncology group made up?
* 2. Which are the causes of brain cancer?
* 3. Is brain cancer hereditary?
* 4. Is there prevention for tumours of the Central Nervous System?
* 5. Is there a more frequent age to develop a tumour in the Central Nervous System?
* 6. Which are most frequent symptoms of a tumour in the Central Nervous System?
* 7. How are tumours of the brain and spinal cord diagnosed?
* 8. Are there complementary studies that help to make a diagnosis?
* 9. How is the definitive diagnosis carried out?
* 10. How is a biopsy performed?
* 11. What types of primary tumors are there in the Central Nervous System?
* 12. What does Low, Intermediate or High-Grade mean in a tumour?
* 13. What questions should the patient ask the physician, once the diagnosis is made?
* 14. Which they are the types of treatment used when a tumour is detected?
* 15. What is Bone Marrow Transplant?
* 16. Which are the possible risks and complications of surgery?
* 17. Which are the collateral and / or secondary effects of chemotherapy?
1. How is a Neuro-oncology group made up?
A true Neuro-oncology group should comprise:
· A Neuro-oncologist, who is a neurologist or oncologist trained in this sub-specialty. He/She is the one who will plan and coordinate the therapeutic options viable for each patient, and will take charge of follow-up. His/Her major role is to administer chemotherapy in cases when it is necessary.
· A Neurosurgeon, a member indispensable for taking decisions of a surgical nature.
· A Neuro-pathologist, the key person who will contribute with the histological diagnosis, starting from the biopsy that the neurosurgeon sends him/her.
· A Neuro-radiologist, the specialist in neuro-images whose report will outline the differential diagnoses arising from the study carried out (Computed Tomography, Magnetic Resonance Imaging, etc.).
· A Neuro-radiotherapist, who will advise and administer most convenient radiotherapy for the patient, if indicated.
· A Neuro-psychiatrist / psychologist, who will have the important responsibility of controlling not only psychiatric disorders caused by the brain lesion, but will also take charge of relieving containing the
patient emotionally.
· A Clinician, who will be in charge of checking the patient, comprehensively embracing all aspects of the human body.
· Nurses and Nurses Practitioners trained in chemotherapy administration, as well as in general care and / or palliatives of the neuro-oncology patients.
All this health staff will meet weekly in tumor boards. This will be the place where they will discuss and exchange diagnostic, therapeutic and general care options, in order to offer the patient and his/her relatives the best medical advice related to his/her illness.
2. Which are the causes of brain cancer?
The causes of brain tumors are still unknown. Research workers are trying to solve this problem. So far, they cannot explain why a person develops a brain tumor and another person under the same conditions, does not develop one.
However, several studies with numerous patients, have attempted to show that there are certain risk factors, so that those who are exposed to them will increase the chance of developing a brain tumor, as compared with the non-exposed population. These factors are as follows:
· A family history of cancer.
· Occupational exposure (solvents, pesticides, electromagnetic fields).
· Dietary factors, including processed meats, sweeteners, vitamins and mineral supplements.
· Medical history of skull traumatisms and radiotherapy.
· Use of hormones.
· Use of cellular telephones.
Most of these factors were unable to demonstrate a clear and unequivocal increase in the risk to develop a tumor in the brain.
3. Is brain cancer hereditary?
Brain cancer is NOT hereditary. There is a small group of familial syndromes associated with brain cancer, the Syndromes of Family Cerebral Tumors, a heterogeneous group of disorders characterized by a variety of
systemic manifestations (corporal) associated with a concurrent variety of neoplasias (tumors) of the CNS. Some of these syndromes are classified as neuro-cutaneous syndromes or "phacomatosis."
The term derives of the fact that they include lentiform hamartomas (*) in the iris, the retina or the optic disk (fakov [phakós]): lentil, crystalline). Such syndromes present characteristic lesions in the skin, together with tumors in the CNS.
Many of these family syndromes have been identified in the DNA, disclosing the chromosomes and "faulty" genes that manufacture anomalous proteins responsible for developing the features characteristic of each syndrome. They are:
· Neurofibromatosis (Type 1 [von Recklinghausen's disease])
· Neurofibromatosis (Type 2)
· Retinoblastoma
· von Hippel-Lindau
· Tuberous Sclerosis
· Sturge Weber
· Turcot
· Carcinoma of basal nevoid cells
· Lhermitte-Duclos/Cowden
· Li-Fraumeni
(*) Tumour consisting of an abnormal mixture of the constituent elements of a certain tissue. Their origin is during the stage of embryonic development.
FAMILIAL CEREBRAL TUMOUR SYNDROMES
a. Syndrome: NF I
Characteristic lesions of the CNS: NFI Glioma of the Optic Nerve (see Fig 1), Brainstem glioma, Lisch nodules. Neurofibromina.
Characteristic lesions in the skin: Bright areas with signal (MRI). "café-au-lait" (coffee and milk) spots. Freckles in axillae.
Ophthalmological characteristics: Nódulos de Lisch.
Chromosome: 17q11
Gene: NF1
Protein: Neurofibromina.
b. Syndrome: NFII Schwannomas of the Acoustic nerve (Bilateral). Multiple Meningiomas.
Characteristic lesions in the skin: Subcutaneous Schwannomas.
Chromosome: 22q12
Gene: NF2
Protein: Merlina.
c. Syndrome: Retinoblastoma
Syndrome Characteristic lesions of the CNS: Retinoblastoma Pineoblastoma (trilateral Retinoblastoma).
Ophthalmological characteristics: Leucochoria.
Chromosome: 13q14
Gene: RB1
Protein: RB1.
d. Syndrome: von Hippel-Lindau
Syndrome Characteristic lesions of the CNS: Cerebellar Hemangioblastoma. / spinal cord
Ophthalmological characteristics: Angioma of the retina.
Chromosome: 3p25
Gene: VHL
Protein: VHL.
f. Syndrome: Tuberous Sclerosis
Syndrome Characteristic lesions of the CNS: Giant cell subependymal Astrocytoma.
Subependymal Nodules. Cortical Tubers.
Characteristic lesions in the skin: Facial Angiofibroma. Hypochromic stains. Sebaceous adenoma. Shagreen patch. Periungueal Fibroma.
Ophthalmological characteristics: Retinal Astrocitoma
Chromosome: 9q34/16p13.3
Gene: TSC1/ TSC2
Protein: Hamartina.
g. Syndrome: Sturge-Weber
Syndrome Characteristic lesions of the CNS: Leptomeningeal Angiomatosis. Cortical calcifications. Hemispheric atrophy.
Characteristic lesions in the skin: Facial Nevus (port wine colour)
Ophthalmological characteristics: Choroidal Hemangioma. Glaucoma.
h. Syndrome: Turcot
Syndrome Characteristic lesions of the CNS: Gliobastoma BPT (type I). Medulloblastoma BPT (type II). 5q21APC
Chromosome: 5q21
Gene: DNA repair/ APC
i. Syndrome: Basal Cell nevoid Carcinoma (Gorlin)
Syndrome Characteristic lesions of the CNS: Medulloblastoma (Gorlin). Carcinoma of basal cells.
Chromosome: 9q22.3
Gene: PTC
j. Syndrome:Lhermitte-Duclos/ Cowden
Syndrome Characteristic lesions of the CNS: Muco-cutaneous Lesiones (Trichilemmomas).
Chromosome: 10q23.3 ( Cowden sindrome)
Gene: PTEN
k. Syndrome: Li-Fraumeni
Syndrome Characteristic lesions of the CNS: Malignant Glioma / PNET 17q p53
Chromosome: 17q (among exons 5-9)
Gene: p53
*(Fig 1. Optic Nerve Glioma)
Treatments for these syndromes not yet have been developed, but with the recent advent of the genetic map deciphered by investigators, Genetic Engineering and Molecular Biology will contribute in a not very distant future, to delineate therapies for the possible cure and eradication of such syndromes.
4. Is there prevention of Central Nervous System tumours?
There is no defined cause for these types of tumours that justifies their prevention. However, it is important to recognize hereditary syndromes, so that once the diagnosis is made, the physician can formulate genetic advice for the patients who are carriers of the syndrome and wish to procreate. This advice consists in warning about the possibility of transmitting the illness genetically to their descendants.
5. Is the any more frequent age group to develop a tumor in the Central Nervous System?
Although brain tumors can occur at any age, several studies have shown that there are two more frequent age groups. The first group is in children from 3 to 12 years; and the second one in adults from 40 to 70 years.
6. Which the most frequent presentation symptoms of a tumour in the Central Nervous System?
The symptoms of the brain tumors depend mainly on the size and localization of the lesion. The symptoms are caused both by damage to vital tissues, and by the pressure exerted by the tumor growing within a limited space in the skull. Such symptoms can also be generated by oedema, that is the water that develops around the tumor, as well as by hydrocephalia, that is a condition that occurs when the tumoral mass or the tumor cells, hinder the normal circulation of the cerebrospinal fluid (CFS) within the ventricular system. This last process can develop due to an excess of production, lack of reabsorption or obstruction of this fluid within the ventricular system, causing an increase in the ventricles of the brain.
The symptoms that all these processes generate are the following ones:
· Migraines (they tend to be worse in the morning).
· Convulsions.
· Nausea and / or vomiting (they are also usually greater in the morning).
· Weakness or changes in normal sense (anaesthesia, parhestesias, pain, etc.) of arms or legs.
· Lack of coordination when walking.
· Dizziness, vertigos.
· Double or blurred vision, partial loss of the field of vision (hemianopsia) or involuntary movements of the eyes (nystagmus).
· Changes in personality.
· Loss of memory.
· Difficulty for speech articulation (dysarthria), or changes in language (dysphasia).
All these symptoms can be shared by other CNS illnesses, and only a physician will be able to discern whether the cause is a tumor or some another disease.
7. How are tumors of the brain and spinal column diagnosed?
To find the cause of the symptoms mentioned above, the physician should ask the patient about his personal and family history in general, as well as to gather data of the history related with cancer. Data were introduced into a correct neuro-oncological history, where together with an exhaustive general and neurological examination, they will guide the professional toward the cause of symptomatology.
8. Are there complementary studies to help diagnosis?
Yes. Once the physician carries out the neuro-oncological history, a series of studies are available that will strengthen the clinical presumption, which include:
· Computed Tomography (CT) of the Brain: a series of images of the brain are reconstructed by a computer after a very short session (it depends on the equipment) of X-rays emitted by a tomograph. In many cases, the incorporation of endovenous iodine as radio-opaque medium, will help the diagnosis.
· Magnetic Resonance Imaging (MRI) of the Brain: at the present time it is the study of choice for the diagnosis of these illnesses. The high power of resolution and sensitivity of this study for CNS tumors make it the gold standard of imaging procedures. Besides, it has the advantage of being an option for people allergic to the iodine. A radio-opaque medium called endovenous Gadolinium is also commonly used, which practically lacks any collateral effects.
· Angiography: at the present time, it is a study that is not carried out routinely when there are strong suspicions of a tumor. On occasion, it can collaborate with the surgical planning for accurate approach, if it is a highly vascularized tumor. Magnetic Angio-resonance imaging is another of the options afforded by MR, in which images of the cerebral vessels are achieved which, depending on the quality of the study and the localization of the pathology, could replace the angiography. Angio-MRI presents a smaller risk, because although gadolinium is injected, this is done in a small peripheral vein, unlike angiography where iodine is injected and in a vessel of greater caliber.
· Spectroscopy: it is habitually carried out together with MRI, and provides information about the behaviour of amino acid metabolism in the brain, helping to differentiate normal cerebral tissue from tumoral recurrence or necrosis (cell death). It also collaborates with the differentiation of the tumors grade.
· SPECT / PET: these studies disclose the metabolism of glucose in the brain. They are mainly used in neuro-oncology to differentiate effects of cerebral radiotherapy (scarring, necrosis) from tumoral recurrence.
· Bone Scan: it is used as a means of tumoral metastases detection
· Myelography: Currently, it is in disuse. It was used to diagnose tumors of the spinal cord, but with the advent of MRI this study it is of scant usefulness.
9. How is the definitive diagnosis carried out?
The definitive diagnosis is carried out by the neuropathologist, by means of the tissue or surgical specimen (BIOPSY) that the neurosurgeon sends him/her. The pathologist takes charge of processing the sample with diverse stains and if necessary with molecular and genetic markers that contribute to provide a definitive diagnosis of the patient's illness. The physician in charge of the patient's follow-up is given a histo-pathological report of the analysed sample and starting from there the neuro-oncological strategy is developed. There are exceptions when it is not possible to carry out a surgical procedure, nor to collect a small tissue sample for biopsy, because the localization of the tumor is risky. In these cases imaging, particularly MRI, is of a great value to help clarify the diagnosis, because most of these lesions have typical patterns of configuration in the CNS.
*(Fig. 2. Meningioma attached to the dura mater)
*(Fig. 3. Meningioma (surgical specimen))
*(Fig. 4. Histology: Diverse meningioma types)
10. How is a biopsy performed?
There are 2 basic types of procedures:
· “Open sky” biopsy
· Stereotaxic biopsy
The first one is generally carried out during the same surgical act of removing the lesion (conventional surgery). A portion of this surgical specimen is analysed later on by the neuropathologist (deferred biopsy). This procedure has the advantage that in the case the lesion is actually a tumor, that in the same act part of the treatment is being carried out, that is to say the surgery.
The second procedure is usually performed when the lesion to investigate is in an important area (eloquent) of the brain, and it is dangerous to carry out an open sky procedure. The biopsy is performed with a special frame that is placed on the skull and allows fixing the head in an ideal position, so that with the help of co-ordinates, the intracranial lesion may be located. A small needle is directed toward the lesion and several samples of the material are extracted to analyse. The neuropathologist habitually carries out at the same time a fast procedure of the sample called biopsy "by freezing." This is a very simple procedure that will give an idea to the pathologist whether the given sample is a tumoral process, and will inform the neurosurgeon if the collected tissue is enough. Thus, he/she collaborates with the neurosurgeon in the decision to conclude the procedure and to increase the chances of success in the diagnosis. As already explained, a deferred biopsy is then carried out with such a sample, where a definitive diagnosis is achieved.
11. What types of primary tumors are there in the Central Nervous System? Brain tumours are classified according to the type of cells composing it and to the histological grade. For some tumors, the location and metastatic dissemination with the cerebrospinal fluid it is also used for the histological classification of cerebral tumours. The classification is as follows:
GLIAL TUMORS (GLIOMAS):
Astrocytic Tumors:
Without Infiltration:
· Juvenile Pilocytic (Low Grade - WHO [*] Grade I -).
· Giant cell subependymal astrocytoma (Low Grade - WHO Grade I -).
· Desmoplastic infantile astrocytoma (Low Grade - WHO Grade I -).
· Pleomorphic xanthoastrocytoma (Low Grade - WHO Grade II -).
*(Fig. 5 Pilocytic astrocytoma)
*(Fig. 6 Giant cell Subependymal Astrocytoma)
Infiltrating:
· Well differentiated diffuse astrocytoma - Fibrillar, Gemistocytic , Protoplasmic - (Low Grade - WHO Grade II -).
· Malignant anaplastic juvenile pilocytic (rare).
· Anaplastic pleomorphic xanthoastrocytoma (High Grade - WHO Grade III -).
· Anaplastic malignant astrocytoma (High Grade - WHO Grade III -).
· Glioblastoma multiforme (High Grade - WHO Grade IV -).
· Gliomatosis cerebri.
*(Fig. 7. Astrocytoma G II)
*(Fig. 8. Glioblastoma Multiforme)
Oligodendroglial tumors:
· Well differentiated oligodendroglioma (Low Grade - WHO Grade II -).
· Anaplastic oligodendroglioma (High Grade - WHO Grade III -).
Ependymal tumors:
· Mixopapillar (Low Grade - WHO Grade I -).
· Subependymomas (Low Grade - WHO Grade I -).
· Well differentiated ependymoma (Low Grade - WHO Grade II -).
· Anaplastic ependymoma (High Grade - WHO Grade III -).
*(Fig. 9. Subependymoma)
*(Fig. 10. Ependymoma)
Mixed tumours:
· Oligo-astrocytoma (Low Grade - WHO Grade II -)
· Anaplastic oligo-astrocytoma (High Grade - WHO Grade III -)
· Ependymo-astrocytoma, Oligo-astro-ependymoma (rare).
NEURONAL AND GLIO-NEURONAL TUMOURS (mixed):
· Dysembrioplastic Neuroepithelial Tumour - DNET - (Low Grade - WHO Grade I -)
· Gangliocytoma or Ganglioglioma (Low Grade - WHO Grade I -).
· Ganglioglioma (Low Grade - WHO Grade II -).
· Central Neurocytoma (Low Grade - WHO Grade II -).
· Desmoplastic infantile ganglioglioma.
· Ganglioneurocytomas, Ganglioglioneurocytomas (mixed).
*(Fig. 11. Ganglioglioma)
EMBRYONAL TUMOURS:
Primitive Neuroectodermic Tumors (PNET´s):
· Medulloblastoma (Classic and Desmoplastic).
· Supratentorial/brainstem PNET.
· Ependymoblastoma.
· Pineoblastoma.
· Medullomyoblastoma.
· Cerebral neuroblastoma.
· Medulloepithelioma (High Grade - WHO Grade IV -).
· Atypical Teratoid/Rabdoid tumor
· Epidermoid/dermoid tumors.
*(Fig. 12. Medulloblastoma)
*(Fig. 13. Pineoblastoma)
MENINGIOMAS:
· Meningothelial (Low Grade - WHO Grade I -).
· Fibrous (Low Grade - WHO Grade I -).
· Transitional (Low Grade - WHO Grade I -).
· Psammomatous (Low Grade - WHO Grade I -).
· Angiomatous (Low Grade - WHO Grade I -).
· Microcystic (Low Grade - WHO Grade I -).
· Secreting (Low Grade - WHO Grade I -).
· Meningioma rich in Lymphoplasmocytes (Low Grade - WHO Grade I -).
· Metaplasic (Low Grade - WHO Grade I -).
· Atypical (Moderate Grade - WHO Grade II -).
· Clear Cell (Moderate Grade - WHO Grade II -).
· Chordoid (Moderate Grade - WHO Grade II -).
· Rabdoid (High Grade - WHO Grade III -).
· Papillar (High Grade - WHO Grade III -).
· Anaplastic or Malignant Meningioma (High Grade - WHO Grade III -). [*] WHO: World Health Organization
*(Fig. 14a. Sphenoidal Meningioma)
*(Fig. 14b. Meningioma of the convexity)
NON-MENINGOTHELIAL MESENCHYMAL TUMORS:
· Tumors of the adipose tissue:
· Lipomas.
· Fibrolipomatous hamartoma.
· Angiolipoma.
· Epidural lipomatosis.
· Intracranial liposarcoma.
Fibrohistiocytic Tumors:
· Fibrous histiocytoma (benign and malignant).
Fibrous tumors:
· Solitary fibrous tumor.
· Intracranial hypotrophic pachymeningitis.
· Fibrosarcoma.
Muscle forming tumors:
· Leiomyoma.
· Intracranial leyomyosarcoma.
· Rabdomyoma.
· Embryonal rhabdomyosarcoma.
· Malignant ectomesenchymoma.
Osteocartilaginous Tumors:
· Chondroma.
· Osteoma.
· Osteochondroma.
· Mesenchymal chondrosarcoma.
· Osteosarcoma.
Vascular tumors:
· Hemangiomas.
· Epithelioid hemangioendothelioma.
· Angiosarcoma.
· Kaposi's sarcoma.
*(Fig. 15. Hemangioblastoma)
Tumours of indefinite histogenesis:
· Hemangiopericytoma.
· Capillary hemangioblastoma.
· Meningeal sarcoma/sarcomatosis.
Melanocytic Tumours:
· Diffuse melanocytosis.
· Melanocytoma.
· Primary leptomeningeal malignant melanoma.
NERVE SHEATH TUMORS:
· Schwannoma (Neurilemoma).
*(Fig. 16. Schwannoma)
PINEAL GLAND TUMOURS:
· Pineocytoma.
· Pineoblastoma (Embryonal Tumors).
PITUITARY TUMORS:
· Pituitary adenoma.
· Pituitary carcinoma.
GERMINAL CELL TUMOURS:
· Pure germinoma.
· Embryonal carcinoma.
· Choriocarcinoma.
· Endodermic sinus tumor.
· Teratoma (Mature or Immature).
Mixed.
CHOROID PLEXUS TUMORS:
· Choroid plexus papilloma (Grade I).
· Choroid plexus papilloma - Atypical or Anaplasic - (Grade II).
· Choroid plexus carcinoma (Grade III).
DERIVATIVE RATHKE SAC TUMORS:
· Craniopharyngioma.
NOTOCHORDA TUMORS:
· Chordoma.
· Chondroid chordoma (Low Grade of mixoid chondrosarcoma).
LYMPHOID CELL TUMOURS:
· Primary Non-Hodgkin lymphoma of the CNS (origin "B" cells)
· Sporadic
· Epidemic (associated to AIDS)
*(Fig. 17. Lymphoma associated to AIDS)
RARE:
· Primary Non-Hodgkin lymphoma of the CNS of Low Grade (origin "B" cells)
· Primary Non-Hodgkin lymphoma of the CNS (origin "T" cells)
· Primary Hodgkin lymphoma of the CNS
CYSTS:
· Colloid Cyst.
12. What does Low, Intermediate or High grade mean in a tumor?
Tumors are classified by the World Health Organization (WHO) in three different grades according to their histology (Low, Intermediate or High). This depends mainly on the cellular features of the tumor; degree of cellular differentiation (well differentiated, metaplasic, atypical, anaplastic, etc.); cellular proliferation (mitosis), and percentage of same; development of vessels within the tumour (vessel neoformation); death of the tumoral cells (necrosis); and their aggressiveness (invasion / infiltration) in the brain. All these factors contribute to typify the tumors according to grades, and in great measure indicates their evolution and prognosis. In general a tumor of high grade has a worse prognosis that one of lower grade.
13. Which are the questions that the patient should ask the physician, once the diagnosis is made?
· What types of treatments will I receive?
· Which are the benefits of such treatment?
· Which are the risks and collateral effects of such treatment?
· How can I prevent such collateral effects?
· Is there any investigation protocol, different from the conventional treatment?
· Will I have to change my daily activities and my way of life in general? If so, for how long?
· How many times will I need to visit the physician for checkups?
· Is there any possibility of cure with this strategy?
These are some of the questions that the patient and / or his/her family should ask when consulting the professional. It is possible that many of the proposals offered by the professional, may not be totally clear at the first visit. These illnesses are very complicated and successive consultations are required, to begin to incorporate the strategy developed by the Neuro-oncologist to attempt to combat the illness.
14. Which are the types of treatment that are used when a tumour is detected?
The treatments that are used depend exclusively on the tumor type to be treated. Basically, there are 3 types of treatments:
· SURGERY
· CHEMOTHERAPY
· RADIOTHERAPY
Surgery continues to be the pillar of neuro-oncology treatment. It has 2 objectives. The first one is to determine the histological type of the tumor that is suspected by means of a biopsy. The second objective is to remove the greatest portion of the macroscopic lesion, that is to say the one observed in images that helped to detect it (CT, MRI, etc.), and by direct observation of the neurosurgeon intraoperatively. Of course, these objectives are carried out in the measure that they don't affect the patient's quality of life.
As documented by several international studies, with an appreciable number of patients, that the quantity of tumoral tissue that is removed by this procedure is in most cases directly proportional to longer survival of the patient.
At the present time, chemotherapy plays a major role in the treatment of all patients with a tumor in the CNS. This treatment consists in the use of drugs to attempt to eliminate tumoral cells remaining after the surgical act. These cells infiltrate microscopically the brain beyond the lesion visible at surgery, and they are responsible for causing recurrence (reappearance) of the illness.
There are several types of drugs used in CNS cancer. Many are used alone, or in most cases they are combined.
Some drugs are even alternated or administered concomitantly with radiotherapy.
Chemotherapy is administered in the form of pills or capsules by mouth, and also on occasion in intravenous form. There are also chemotherapic drugs implanted in the tumor bed during the same act when surgery is carried out. On other occasions, chemotherapy can be introduced in the fluid that surrounds the brain and the spinal cord (cerebrospinal fluid), by means of a special needle, in intervertebral spaces in the column (intrathecal chemotherapy).
The treatment is generally performed with drugs and conventional schedules, or with protocolized schedules of drugs (new or well-known) and novel drug combinations. These last ones are the Protocols of Investigation.
As a rule, chemotherapy is administered in a certain number of cycles that vary in quantity and time, according to the schedule used for each illness. In general, cycles last from 4 to 6 weeks, in each of which the drugs are administered in the first days of the cycle, and then the patient begins a "rest" period of medication
until beginning the new cycle. Once the schedule planned by the neuro-oncologist is completed, the latter will decide, according to the patient's evolution, which is next step to continue.
In general, when it is sought to obtain an acceptable survival, there are three periods:
· Induction
· Consolidation
· Maintenance
The first period (induction), consists in administering a certain quantity of chemotherapy cycles, according to the histological type of the tumor. The idea is to eliminate the greatest possible quantity of malignant cells, seeking that the cancer should pass to a remission stage (involution).
The second (consolidation) is in general a period where a high chemotherapy dose is administered intensively (greater than in induction), where it is sought to eliminate any residual tumor cells.
The third period (maintenance) is to attempt to "chronify" the illness, maintaining small quantities of chemotherapy, during a lengthy period of time, attempting to prevent reappearance of the illness,
maintaining the patient in remission.
The Radiotherapy is a treatment that has been used for approximately one century. It has evolved with scientific advances in computation and in physics, leading to a most remarkable improvement in equipment, precision, quality and indication of treatments.
This treatment consists in the use of X-rays or other rays of high energy, to eliminate malignant cells and to reduce tumors after surgery, or when the latter is not possible. Two basic ways exist for radiotherapy administration:
· External radiotherapy or Teletherapy, in which the radiation source is at a certain distance from the patient, and is emitted by equipment of great dimensions. These are the linear accelerators. The radiation emitted consists of photons (X-rays). This treatment type is the most frequently used, and patients are subjected to daily sessions of a few minutes, generally during a period of 5 continuous times per week, during 6 weeks.
· Interstitial brachytherapy: the radiation source is placed on the tumor bed, generally at the same surgical time. Habitually radio-active seeds are used that contain 125-Iodine with the capacity to emit gamma rays. Other energy types have also been used like beta radiation (32-P, 186-Rhenium, etc.). Depending on the material used, the radio-active implant can be left in the brain for an established period of time or permanently. Implants lose radioactivity day after day. This procedure requires hospitalization for a brief period of time that coincides with the post-operative period and with the period when the radiation is more active. It is for this reason that relatives can require special suits when they visit the patient in this period. This treatment type is not widely used, probably due to complexity of its instrumentation, to its collateral effects (greater than with conventional radiotherapy) and because there is no demonstrated greater effectiveness.
Stereotaxic radiosurgery, also called Gamma-Knife, is another of those radiotherapy forms to treat some brain tumors. It is a treatment form developed by the integration of knowledge from several medical specialties: Neurosurgery, Radiotherapy, Radiology and Medical Physics. The administration of radiation is in a single session. It consists of a high radiation dose, but it is only directed to the tumour. This is achieved by fixing the patient's head with a special frame (stereotaxic frame), where with the help of imaging (MR), co-ordinates are achieved that will direct the rays toward the exact site of the lesion, avoiding damage with secondary radiation to normal brain tissue that surrounds the tumor. The rays are of gamma type and they come from an external source of cobalt. In general, it is useful in small tumoral lesions which are not surgically accessible. It is used in some specific tumors and generally in their recurrences.
15. What is Bone Marrow Transplant?
A novel treatment is available for patients with malignant tumors, called bone marrow transplant and autologous stem cell rescue (mother cells). This procedure consists basically in administering
high chemotherapy doses during a brief period of time (3-8 days), followed by reinfusion of stem cells of the patient. Prior to chemotherapy administration, an established quantity of stem cells are extracted from the patient's peripheral blood (leukopheresis). The possibility also exists of obtaining stem cells from the patient's bone marrow, by means of a complex laboratory process.
Once this material is obtained, it is preserved at temperatures below zero, until the moment of reinfusion of such cells (transplant).
The objective of this treatment is to be able to administer very high doses (myeloablative) of chemotherapy, only tolerable for the organism if previously stem cell rescue is carried out for later reinfusion. This procedure causes the "temporary" ablation (disappearance) of the patient's bone marrow. Otherwise, the administration of such chemotherapy doses would be impracticable, which although they be more efficacious that conventional doses on cerebral tumours, they would be incompatible with life.
This therapy this directed to a very select group of patients and is mainly used in paediatric tumors. However, at the present time, there are carefully designed investigation protocols that comprise a wide range of ages and of tumoral diversity.
16. Which are the possible risks and complications of surgery?
The surgery is necessary for most CNS tumors. On occasion, there may occur surgical complications and in other cases undesirable effects can appear, but these are to be expected every major surgery. Such risks include:
· Bleeding of the surgical bed
· Cerebral oedema
· Convulsions
· Infection
· Appearance or worsening of previous neurological deficits.
Quite often, neurological signs and symptoms can worsen after surgery. Most of them resolve in the short term. In rare cases, a surgical reintervention is necessary in the post-operative period (e.g., bleeding of the surgical tumor bed), to solve some complications that pose a risk for the patient's life.
All risks related with the surgical procedure are minimal with expert physicians. Undesirable effects (e.g., oedema, convulsions, etc.), are perfectly controllable with medication.
17. Which are the collateral and / or secondary effects of chemotherapy?
The collateral and / or secondary effects of chemotherapy depend mainly on which drug is administered and not all produce the same effects. Even the same drug administered at different doses will cause different effects. In general antitumoral drugs not only destroy the tumoral cells, but they also affect the cells that
they divide quickly in the organism, as the cells of the blood (red blood cells, white blood cells, platelets), cells of the digestive tract and cells of the hair follicle. As a result of these complex effects, the patient can experience collateral symptoms, classified according to the frequency of presentation:
· Common (>20%).
· Occasional (5-20%).
· Rare (<5%).
According to the time of presentation:
· Immediate (within 24-48 hours).
· Fast (in 2-3 weeks).
· Deferred (at some time during therapy [excluding the above]).
· Late (at some time after completing treatment).
All effects combine, alternate, diminish, and even disappear, depending on the type of chemotherapic schedule administered. The signs and symptoms described below don't follow an order of frequency.
· Fatigue and loss of energy (caused by anaemia).
· Fever and infections (decrease in white blood cells).
· Spontaneous haematomas, small bleeding (e.g., gums, increase in quantity of blood with menstruation, etc.).
· Nausea and / or vomiting.
· Diarrhoea (fast turnover of intestine cells).
· Loss of hair (fast turnover of the follicle cells).
· Loss of appetite.
· Renal problems.
· Auditory problems.
· Infertility.
All these symptoms can be controlled, minimised and even avoided, because at the present time there are enough drugs to help achieve an oncological strategy, with an acceptable quality of life.
This is the challenge undertaken by the neuro-oncologist, when treating a patient with CNS cancer.
18. Which are the possible collateral effects of Radiotherapy?
The effects of conventional radiotherapy are largely produced by the effects of the rays that impact on the healthy area that surrounds the tumor (secondary radiation). Nowadays, there are techniques called
conformational, in which computer-assisted designs of the tumoral area to irradiate are in millimetres, thus avoiding damage to normal brain structures neighbours to the tumour. Such undesitable effects can be acute / subacute:
· Fatigue.
· Nausea.
· Migraines.
· Dizziness.
· Convulsions.
· Irritation of the skin.
· Fever and infection.
· Somnolence.
· Loss of appetite.
· Loss of hair: Temporary, with poor recovery quality.
Chronic:
· Difficulties in learning and normal development (frequent in children).
· Ophthalmological and auditory difficulties.
· Loss of memory.
· Endocrinological problems.
· Dementia.
These collateral effects (mainly the acute ones), the same as with chemotherapy, watched over by the physician in change, can be minimised with medication. For example, corticoids are very frequently used to diminish the oedema caused by radiotherapy in the brain.
Long-term unwanted effects (chronic) are more difficult to control. It is for this reason that radiotherapists continues perfecting constantly the techniques of ray emission, so that the "target" (lesion to irradiate) is more and more precise.
19. Which are the concomitant medications that are added the main treatment?
There is a series of medications that are habitually added to the neuro-oncological schedule. They are:
· Esteroids: they help to reduce cerebral oedema.
· Anti-seizures: they are the drugs administered to control convulsions.
· Anti-emetics: they control nausea and vomiting.
· Antacids: they annul stomach acidity caused by the steroids and prevent the development of duodenal ulcers.
· Analgesics: they are administered for headaches, or neuropathic pains.
· Hormonal: they replace the normal secretion of hormones of the organism.
After surgery, the removal of a tumor located in a gland, can cause the decrease or the annulment of hormonal secretion. In this case it is necessary to replace them with hormonal medication.
20. Do brain tumors cause metastases?
It is extremely rare that primary brain tumours (originating in CNS cells) cause metastases in other localizations of the human body. Surprisingly, metastases in the brain coming from another cancer originating in another organ, represent the most frequent intracranial tumors, even exceeding the incidence of primary cerebral tumours.
Men and women are affected in general in the same way, and the peak of incidence to develop metastases in the CNS is between the fifth and seventh decade of life.
21. Where do cerebral metastases come from?
In adults, the most common sites of metastasic origin are the following:
· Lung.
· Breast.
· Skin (Melanoma).
· Colon.
· Kidney (renal clear cell carcinoma).
*(Fig. 18. Metastases)
In children the most common sites of origin within solid tumors are:
· Sarcomas.
· Germinomas.
22. How are metastases in the brain treated?
By and large, the therapeutic schedule of cerebral metastases depends on the stage and on the basic treatment of the original cancer.
As general rules when the patient's expectation of life is limited by the progression of the primary illness or there is extra-cranial metastases, the most reasonable option is palliative treatment.
This consists in offering comfort, reducing with medications the symptoms that limit the quality of life (see concomitant medication). However, when the expectation of life is from 6 to 12 months, patients can be benefited with whole brain radiotherapy, or chemotherapic schedules, if the original tumour responds to such drugs.
Patients with a good prognosis, a few well defined metastases, can benefit with aggressive surgical strategies, combined with radiotherapy protocols and chemotherapy, attempting to achieve local control of the disease.
23. What are the paraneoplastic syndromes?
There is a group of neurological illnesses that are defined as paraneoplastic syndromes, when they occur in patient with cancer (leukemias, lymphomas, multiple myeloma, neuroblastoma, small-cell lung, testicle, prostate, breast, endometrium, kidney, etc.) and they are not related with metastases, infection, metabolic abnormalities or of the treatment toxicity.
They represent a dysfunction of the nervous system, related with humoral and / or cellular immunity disorders (antibodies and cells in charge of the immune system). Most of these syndromes have one or several antibodies and / or antigens in the blood that identifies them.
Although these syndromes are relatively rare, their correct diagnosis is of crucial importance. There are three main reasons that support such a statement. The first one is that such syndromes are the first warning of a hidden neoplasia, and they can even anticipate in years the clinical evidence of cancer. The second reason, is that an early diagnosis allows administering immunomodulator or immunosuppressor treatments, before irreversible neurological deficits may occur. And lastly, to confuse a paraneoplastic syndrome with a metastastic complication or as a result of a collateral / secondary effect of chemotherapy or radiotherapy, can lead to erroneous therapeutic decisions.
Paraneoplastic syndromes are as follows:
· Neuronopathy - Subacute Sensory Encephalomyeloneuritis.
· Limbic Encephalitis / Encephalitis-Myelitis of the Brainstem.
· Autonomic Neuropathy.
· Anti-Hu Syndrome.
· Progressive Cerebellar Degeneration.
· Visual Paraneoplastic Syndrome.
· Opsoclonus-Myoclonus.
· Paraneoplastic Disorders of the Motor Neurone.
· Paraneoplastic Peripheral Neuropathy.
· Mixed Subacute Neuropathy (sensory-motor).
· Acute Polyradiculoneuropathy.
· Neuropathies associated with Plasmatic Cell Discracias.
· Multiple Mononeuritis and Vasculitis.
· Brachial Neuritis.
· Disorders of the Neuromuscular Juncture.
· Eaton-Lambert Syndrome.
· Paraneoplastic Disorders of Movement.
Over the last 10 years there have been significant advances in the clinical classification and the immunobiological understanding of these paraneoplastic neurological disorders. There is no highly effective treatment for most of these syndromes. Immunosuppression with esteroids, plasmapheresis, immunoglobuline G or immunoabsorption are variably effective.
With the hope of finding new therapeutic applications, molecular investigators continue deciphering the behaviour of these syndromes, which will contribute to advances in their treatments in the next few years.
24. May recovery from the neurological deficits caused by the tumour be achieved?
Most definitively. In most cases, patients are referred to a team of neurological rehabilitation. This depends mainly on the patient's stage. However, rehabilitation will help to recover, to a great extent, from the deficits caused by the tumor.
25. What is the advantage of signing up in a Research Protocol?
At the present time, the neuro-oncological clinical investigators are developing new chemo-radiotherapeutic strategies. The main objective is to increase the survival of patients with CNS tumors.
The investigation protocols afford the possibility to participate together with a select group of patients, in novel therapeutic strategies, which are challenging the already well-known conventional schedules of treatment.
These protocols have already been assayed previously in experimental animals in successive phases, which offers the patient involved in this strategy, a wide margin of therapeutic safety.
The final objective of the permanent development of these protocols is the "cure" of cancer.
26. References and consulted images:
Michael Prados MD. Book: Brain Cancer, American Cancer Society (Atlas of Clinical Oncology). Editors: Steele GD, Phillips TL, Chabner B. BC Decker, Hamilton, Ontario. 2002, p:426
*(Fig. 2. Meningioma attached to the dura mater)
*(Fig. 3. Meningioma (surgical specimen))
*(Fig. 4. Histology: Diverse meningioma types)
*(Fig. 5 Pilocytic astrocytoma)
*(Fig. 6 Giant cell Subependymal Astrocytoma)
*(Fig. 7. Astrocytoma G II)
*(Fig. 8. Glioblastoma Multiforme)
*(Fig. 9. Subependymoma)
*(Fig. 10. Ependymoma)
*(Fig. 11. Ganglioglioma)
*(Fig. 12. Medulloblastoma)
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