Central nervous system tumors

Anatomy
Central nervous system

Anatomy

Anatomy
CNS=brain+spinal cord Brain= 1) Supratentorial part: -cerebral hemispheres -diencephalon (1. thalamus, 2. hypothalamus, 3.
epithalamus, 4. prethalamus or subthalamus and 5. pretectum)

2) Infratentorial part: -brainstem -cerebellum

Cerebrospinal fluid
Between pia mater on one side and the arachnoid and dura mater on the other side Produced by the choroid plexuses from the ventricles and reabsorbed by the arachnoid granulations

Epidemiology
90% of brain tumors=metastases from other tumors Only 10% of brain tumors=primary brain tumors This represents about 3% from all cancers In adults 2/3 of primary brain tumors are supratentorial, whereas in children, 2/3 of brain tumors are infratentorial.

I. Genetic risk factors

Neurofibromatosis type 1 (NF1): - schwannomas, meningiomas, and certain types of gliomas, as well as neurofibromas (benign tumors of peripheral nerves). Changes in the NF1 gene cause this disorder. Neurofibromatosis type 2 (NF2): much less common than NF1; is associated with vestibular schwannomas (acoustic neuromas) and, in some patients, meningiomas or spinal cord ependymomas. Changes in the NF2 gene are responsible. Tuberous sclerosis: -subependymal giant cell astrocytomas (low-grade astrocytomas that develop beneath the ependymal cells of the ventricles), in addition to benign tumors of the skin, heart, or kidneys. It is caused by changes in either the TSC1 or the TSC2 gene. Von Hippel-Lindau disease: -inherited tendency to develop hemangioblastomas (blood vessel tumors) of the cerebellum or retina as well as tumors of the kidney, adrenal glands, and pancreas. It is caused by changes in the VHL gene. Li-Fraumeni syndrome: -at higher risk for developing gliomas, along with certain other types of cancer. It is caused by changes in the p53 gene. Other inherited conditions, including Gorlin syndrome, Turcot syndrome, and Cowden syndrome are also linked with increased risks of certain types of brain and spinal cord tumors. Other families may have genetic disorders that are not well recognized or that may even be unique to a particular family.

II. Environmental risk factors

1. Ionizing radiation is the only unequivocal risk factor that has been identified for glial and meningeal neoplasms. Irradiation of the cranium, even at low doses, can increase the incidence of meningiomas by a factor of 10 and the incidence of glial tumors by a factor of 3 to 7, latency period of 10-20+ years after exposure

2. Lack of proper exercise and obesity during teen years 3. Taller people have brain tumors more frequently
Both of the data comes form the NIH-AARP Diet and Health Study (~500 000 subjects) Those who reported doing substantial amounts of light, moderate and vigorous exercise between the ages 15 and 18 were 36% less likely to develop a glioma than those who were sedentary. Activities included walking, aerobics, biking, swimming, running, heavy housework or gardening. Who were obese during their teen years had a three to 4 times greater risk of developing glioma than those of a normal weight. It could be that obesity increases the risk of brain cancer, or if could be that some underlying condition increases both the risk of obesity and brain cancer Each 10 centimeter increase in height meant a nearly 20% increase in risk of developing glioma.

4. Cell phone use-microwaves Some of the strongest evidence supporting a link between brain tumors and cell phone use comes from a series of Swedish studies, led by Dr. Hardell Overall. The researchers found that risk increased with the number of cumulative hours of use, higher radiated power, and length of cell phone use. Younger users had a higher risk. In fact, the highest risk was among people who were younger than 20 years at the time of first use. (Int J Oncol. 2006;28:509-518; Int Arch Occup Environ Health. 2006;79:630-639; Arch Environ Health. 2004;59:132-137; Pathophysiology. 2009;16:113-122). A meta-analysis that incorporated 11 long-term epidemiologic studies in this field also reported a link between cell phone use and brain tumors. Using a cell phone for 10 years or longer was positively associated with the development of an ipsilateral brain tumor; in fact, it doubled the risk (Surg Neurol. 2009;72:205-214)

5. Presence of allergy decreases the risk risk of glioma

-2007 study: relative risks (RRs) of glioma comparing people with a history of an atopic condition with people with no history of atopy were 0.61 for allergy, 0.68 for asthma, and 0.69 for eczema. -no relation between meningioma and allergy

6. Impaired immune system (AIDS) =>

increased risk of developing lymphoma of the brain or spinal cord

Histological subtypes of CNS tumors

Cellular origin Histological subtypes Frequency Age of diagnosis Treatment % survival 1 yr/ 5 yrs

Astrocytes

High grade astrocitomas : -Glioblastoma multiforme (grade IV) -Anaplastic astrocytoma (grade III) Low grade astrocitomas: -Low grade astrocytoma (grade II) -Pylocyitic astrocitoma (grade I)

Most frequent malignant primary brain tumors in adults; 60 years Rare tumors 50 years

Excision RT Chemotherapy

45% < 5% !!! 60% < 10 %

Excision +/- RT Rare tumors 30-40 years Excision

80% 60% >90%

Oligodendrocytes

Anaplastic oligodendrogliomas (grade III) Oligodendrogliomas (grade II)

Rare tumors 50 years

Excision RT Chemotherapy

50% 30%
85% 60%

Histological subtypes of CNS tumors (2)

Cellular origin Histological subtypes Frequency Age of diagnosis
Medulloblastoma
Most frequent primary malignant brain tumors in children (3/4 in children)

Treatment

Prognostic % survival 1 yr/ 5 yrs

Cerebellar cells

Excision 80%/50% +/-Cranio-spinal RT +/-Chemotherapy Excision +/-RT Stereotactic radiosurgery/ Gamma-knife excision +/adjuvant RT 55/45% >95%

Ependimocytes Hypophyseal cells

Ependimoma Hypophyseal tumors -benign/malignant -secreting/nonsecreting

Rare tumors Rare tumors; adults

Meningeal cells

Beningn or malignant Frequent meningiomas tumors; age around 40 yrs; female predominance

>90% for benign tu. <60 % for malignant tumors

Glioblastoma multiforme (grade IV)

The worst prognosis Despite its apparent demarcation on enhanced scans, the lesion may diffusely infiltrate into the brain, crossing the corpus callosum in 50-75% of cases.

Physiopathology
Effect on normal neural tissue: 1. Invasion 2. Compression Edema Necrosis Intracranial hypertension Hydrocephalus The evolution of the disease can be: -slow-months, years (grade I, II) -fast-weeks, months (grades III,IV)

Dissemination routes
Leptomeningeal dissemination: NHL, medulloblastoma, ependimoblastoma. Distant metastases: rare; might be present in medulloblastoma There are no lymphatics in the CNS=>no lymph node metastases!!!

Symptoms
Headache Signs of intracranial hypertension (nausea, vomiting, somnolence) Epileptic seizure Focal neurological signs depending on the localization of the tumor

 Cerebellar symptoms
Most commonly found in children, the tumor involves the cerebellar vermis and causes gait ataxia more readily than unilateral symptoms. Adults more commonly harbor the desmoplastic variant of medulloblastoma, which arises in the cerebellar hemisphere. These patients often have symptoms of ipsilateral dysmetria (undershoot or overshoot of
intended position with the hand, arm, leg, or eye)

 Leptomeningeal dissemination
Presenting symptoms rarely are related to dissemination of tumor in the CSF. Patients can complain of severe weakness from tumor compression of the spinal cord or nerve roots (eg, radiculopathy).

Diagnostic work-up (1)

MRI with gadolinium contrast of the skull

Search for an other primary which can give a CNS metastasis General laboratory work-up, performance index Tumor biopsy/excision

Diagnostic work-up (2)

Lumbar puncture for NHL, medulloblastoma, ependimoblastoma Ophthalmoscopy - optic disc=where the nerves of the eye converge to pass to the brain. Normally: clearly-defined, pale concave disc, but if the pressure in the CSF is raised, the disc may bulge forwards into the cavity of the eye = papilledema Campimetry Search for distant metastases (medulloblastoma)

Treatment
High grade gliomas: maximum safe resection adjuvant radiotherapy and chemotherapy with temozolomide younger pacients have better prognosis Low grade gliomas, meningiomas: Resection +/- adjuvant radiotherapy Hypophyseal tumors: Stereotactic radiosurgery/ Gamma-knife

Contouring on fused CT/MRI image

Gamma-knife

Proton therapy

Side effects of RT
ACUTE: edema Increased intracranial pressure CHRONIC: Necrosis of brain tissue In children: decreased IQ Adults: decreased mental functions

Questions
What is the most frequent primary brain tumor in adults? And in children? What CNS tumors disseminate through de CSF? Enumerate some negative prognostic factors for CNS tumors. (Answer: older age, high grade histology (III, IV), larger residual tumor, lower performance index). What is the treatment sequence for high grade gliomas?