radiation

Meningioma and the Arachnoid Cap Cell

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A meningioma is a tumor that arises from the lining of the brain or spinal cord (ie: the “meninges”). They arise from cells known as “arachnoid cap cells”. Meningiomas are usually slow growing, “benign” tumors, which means that they are not usually considered cancerous in the strictest sense of the term.

When viewed under the light microscope, meningiomas can have many different appearances. The most common type is a dense sheet-like formation of cells interspersed with closely packed blood vessels. Sometimes the sheets of cells can be separated by connective tissue.

Frequently, meningiomas will have calcium deposits in them known as “psammoma bodies”. Uncommonly, meningioma cells may take on a malignant appearance characterized by increased cellular division (ie: “mitotic figures”) and invasion of the tumor cells into surrounding brain or bone.

Meningiomas test positive for epithelial membrane antigen (EMA) and vimentin (a marker of connective tissue). Ki-67 (a marker of proliferation) can be elevated in more aggressively behaving tumors.

The most common genetic abnormality seen in patients with meningiomas is found on chromosome 22. If present, a mutation in the NF2 gene on this chromosome causes type 2 neurofibromatosis. This disease predisposes individuals to developing multiple tumor types including meningiomas. Other less common genetic abnormalities can be seen on other chromosomes as well.

Signs and Symptoms

Due to their slow growing and benign nature, many meningiomas cause no symptoms. However, if they become too large or start to compress adjacent brain tissue they can cause headache, seizures, confusion, or visual problems. Spinal cord compression can result in myelopathy.

The most common location for a meningioma is in between the two hemispheres of the brain – the so called “parasagittal” location. Parasagittal meningiomas near the portion of the brain responsible for muscle movements may cause weakness of the opposite leg.

Diagnosis

Diagnosis of meningioma can reliably be made on characteristic findings seen on CT or MRI scans. Interestingly, many meningiomas are found incidentally when a CT or MRI is done for other reasons.

Meningioma MRIs

However, like any other tumor, meningiomas can only be truly diagnosed once a specimen is sent to the pathology lab for analysis. Pathologists can reliably make the diagnosis based on typical histological features.

Meningiomas must be distinguished from a more malignant tumor known as a hemangiopericytoma. Hemangiopericytomas can look similar to meningiomas on imaging studies.

Dish Me Up Some Treatment Sir

Many meningiomas can be watched over time with repeat imaging studies; this is especially true if they are small and not causing neurological signs or symptoms.

On the other hand, large or symptomatic meningiomas require surgical resection. Many meningiomas can be removed completely. However, some meningiomas may be near vital structures such as the carotid artery, cranial nerves, or venous draining systems of the brain where complete surgical removal may be very difficult without causing significant neurologic impairment. In these cases the tumor is debulked as much as possible. The residual tumor can be followed or irradiated depending on the grade of meningioma.

Residual tumor after incomplete surgical resection, or meningiomas in difficult to access locations are candidates for radiation therapy. Many studies have shown long term growth control rates.

Overview

Meningiomas are considered “benign” tumors of the brain. They arise from arachnoid cap cells, which are located in a layer of the meninges (ie: the covering of the brain) known as the arachnoid. Symptoms include headache, weakness, vision problems, paresthesias (ie: abnormal sensations), amongst many other possible symptoms. Diagnosis can be made reliably from imaging studies such as CT or MRI. If symptomatic, or large, treatment is surgical resection. Small asymptomatic meningiomas can be managed with repeat imaging to assess for growth over time.

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Chordoma and that Pesky Notochord

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In order to understand chordomas we have to first learn a little bit about how the nervous system develops. Enter the notochord.

The notochord is a midline structure in the developing fetus that sends out various molecules (the most well known of which is “sonic hedgehog”). These molecules influence the development of the layers of embryonic cells that surround the notochord. One of these layers, the ectoderm, which is immediately behind (ie: posterior) the notochord eventually forms the brain and spinal cord. The mesoderm, which is immediately adjacent to the notochord forms the vertebral column and axial skeleton (amongst other things).

The purpose of the notochord is to ensure that each layer of tissue forms what it is supposed to. Once this occurs, the notochord ultimately becomes the nucleus pulposus of the intervertebral discs.

In some people, nests of cells that composed the fetal notochord remain (unnaturally) after birth. These collections of cells are known formally as ecchordoses physaliphora (try saying that 5 times fast). These cells can divide and turn into a slow growing tumor… What is that tumor called? You guessed it! A chordoma!

Chordomas are slow growing tumors that are most commonly located at the ends of the vertebral column. The most common place to see them is in the sacrococcygeal region, followed in frequency by a bone known as the clivus at the base of the skull. However, chordomas can occur anywhere along the vertebral column. The reason they occur most frequently at the "ends" of the vertebral column (ie: skull base and sacrum) is because these are the last areas to fuse in-utero.

Additionally, since the notochord is a midline structure in the fetus, chordomas are almost always midline in location.

Microscopically chordomas contain large polygonal shaped cells embedded in a mesh of long repetitive sugar and nitrogen containing molecules known as mucopolysaccharides.

Chordoma Highlights:
– Arise from notochord cells
– S-100 positive
– Cytokeratin positive
– Polygonal cells
– Slow growing
– Midline location
– Sacrum and clivus most
   common locations
– Worse prognosis than
   chondrosarcomas
Less than a third of chordomas will show cartilage like features. These chordomas are classically called “chondroid” chordomas because of the chondrocyte-like (ie: cartilage-like) cells and extracellular material within them. Chondroid chordomas must be distinguished from a similar looking tumor known as a chondrosarcoma.

Distinguishing chondrosarcomas from chordomas is possible with immunocytologic staining techniques. Chondromas and chondrosarcomas stain positive for a protein known as S-100. S-100 proteins have numerous intracellular functions and are commonly present in cells such as adipocytes (fat cells), chondrocytes (cartilage forming cells), melanocytes (pigment producing cells), and Schwann cells, amongst others.

So if chondrosarcomas and chordomas can look alike, and both stain positive for S-100, how the heck do we distinguish between the two? Using another molecule known as cytokeratin! Cytokeratin is a molecule that forms part of the intracellular frame for many cells. It is present in chordomas, but not in chondrosarcomas.

On to the Clinic I Say…

Chordomas are slow growing tumors and will usually start to cause symptoms in mid-adulthood. Symptoms are based on the location of the tumor.

If the tumor is located in the sacrum or coccyx then pain is the most frequent presenting symptom. If undiscovered this may progress to bowel and bladder problems as the tumor slowly envelopes the sacral nerves that go to the bowel and bladder. Additionally, patients may present with radicular symptoms such as numbness, tingling, or sharp pain in the distribution of the sacral nerves.

Clivus Chordoma
Chordomas of the clivus, the second most common location, can present with headache and if large enough symptoms of brainstem or upper cervical spinal cord compression. These symptoms may include vertigo, difficulty moving the tongue, double vision, hearing problems, spastic gait, increased reflexes, clumsiness, amongst other symptoms.

Diagnose Me McCoy

Diagnosis of chordoma can only be officially made by looking at the specimen under a microscope. However, imaging studies with x-rays, CT scans, and MRI imaging can support the diagnosis. Imaging studies will typically show a midline lytic lesion centered in the bone. Invasion of adjacent anatomical structures can occur, but is a late manifestation of the disease course.

Treating These Ugly Tumors

The gold-standard treatment for chordomas is en-bloc surgical resection with wide margins followed by radiation therapy. Complete resection is difficult, if not impossible to achieve in the skull base, but may be possible in the spine and/or sacrum with very skilled surgical teams.

Without an en-bloc surgical resection the risk of tumor re-growth and recurrence is very high. If you are planning to biopsy of a sacral lesion you should mark the biopsy tract with methylene blue so that the tract can also be resected during surgery as tumor cells can seed the tract as the needle is being pulled out.

Let’s Remix This Overview

Chordomas are slow growing, but malignant tumors that arise from notochord cells that fail to regress after birth. They are most frequently found in the sacrum and clivus (one of the bones constituing . Diagnosis is made with CT, MRI, and x-rays, as well as via tissue diagnosis at the time of surgical removal. Chordomas stain positive for S-100 and cytokeratin proteins, which helps distinguish them from chondrosarcomas that only stain positive for S-100. Symptoms are based on where the lesion is located (skull base or spine). Treatment is surgery followed by radiation therapy.

Just Warming Up…

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Cerebral Cavernous Malformations: Leaky Vessels

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Cavernous malformations (aka: cavernomas or cavernous hemangiomas) can be thought of as vascular tumors. They are composed of a capillary-like network of endothelial cells (the cells that normally line blood vessels). However, unlike normal capillaries throughout the body, the capillaries of cavernomas can leak.

Interestingly, cavernous malformations do not have any brain tissue within them. This helps distinguish them from another related vascular abnormality known as an arteriovenous malformation.

The genetics of cavernous malformations have been elucidated by studying familial forms of the disorder. There are at least three known genetic defects that predispose patients to develop cavernomas. These genes appear to be important in the formation of blood vessels (a process known as "angiogenesis") and the blood brain barrier. Therefore, mutations in these genes can cause the abnormal growth of vascular tissue.

What Havock Do These Guys Cause?

Cavernomas can cause numerous signs and symptoms depending on their location within the brain. Seizures are the most common symptom. However, progressive neurological impairment such as worsening weakness can also occur.

Sometimes cavernomas can block the flow of cerebrospinal fluid leading to hydrocephalus. Hydrocephalus can cause increased intracranial pressure leading to headaches, nausea, and vomiting. However, it is important to realize that many patients with cavernomas have no symptoms at all!

If symptoms are present, they tend to progress over time. This is because cavernous malformations bleed and re-bleed resulting in an expansion of its size over time. As the malformation increases in size it can push on adjacent brain tissue causing worsening symptoms.

Unlike arteriovenous malformations, life threatening and severe hemorrhages are rare. Cavernomas bleed at an initial yearly rate of anywhere between 1% to 5%. After the first bleed, the risk of re-bleeding increases to as high as 10% per year. In other words, if a cavernoma bleeds, it is more likely to re-bleed at a later date.

How Do You Diagnose These Buggers?

Cavernoma Marked

The diagnosis of cavernous malformations are made via imaging studies. They are usually detected via MRIs that are ordered for evaluation of neurological symptoms. Cavernomas are seen best on T2 and gradient echo MRI sequences. They typically look like a piece of popcorn.

Select patients undergo a more invasive imaging procedure known as angiography. Angiography is used to rule out another similar lesion known as an arteriovenous malformation. Since cavernomas are venous malformations they are not seen on angiograms.

How Are These Treated?

Depending on the location, most cavernous malformations in the brain or spinal cord are removed surgically. Some institutions offer radiation as a means of treatment, especially in difficult to access areas (ie: where the risk of surgical removal is very high).

Let’s Recap this MoFo

Cavernous malformations of the brain are abnormal vascular growths composed of capillary networks. They are likely the result of genetic mutations in genes responsible for blood vessel growth. Depending on their location they can cause numerous neurological symptoms such as seizures and weakness. MRI often shows the characteristic “popcorn” lesion. Treatment is usually with surgical resection, although some cavernomas may be radiated depending on their location.

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Hemangiopericytoma: A Tumor of Pericytes

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In order to understand hemangiopericytomas we have to define a few terms. The first term is mesenchyma. Mesenchyma is a word used to describe the different tissues that provide structure to the bodies’ organ systems. A type of mesenchymal cell known as a “pericyte” provides structural support to blood vessels. When pericytes go haywire they form hemangiopericytomas.

Hemangiopericytomas can occur anywhere blood vessels are located, but are most commonly located in the lower extremities, pelvis, head, and neck.

Intracranial hemangiopericytomas are uncommon. They represent less than 1% of tumors within the confines of the skull. They typically arise from blood vessels adjacent to the dura (ie: lining of the brain) and often form dural attachments. They are therefore commonly lumped into the category of “dural-based tumors”, but should be distinguished from their more benign meningeal cousins (ie: meningiomas).

Since hemangiopericytomas are mesenchymal in origin, they typically have lots of reticulin (a collagen fiber) that envelopes individual cells (see pathology slide). They are highly cellular tumors, and vascular channels in the shape of "staghorns", may be seen under the microscope. Actively dividing cells (aka: "mitotic" figures) are commonly seen and are a testament to their more malignant nature. Unlike meningiomas, calcifications are absent.

Hemangiopericytomas test positive for vimentin (a marker of connective tissue), Ki-67 (a marker of proliferation), vascular endothelial growth factor (VEGF, a marker of blood vessel proliferation), CD34 (a marker of blood and vascular cell lineage), and reticulin (a collagen fiber). These tumors do not stain positive for epithelial membrane antigen. Genetic mutations have been found on different chromosomes , but the importance of these abnormalities is not well understood.

Intracranial hemangiopericytomas are considered malignant tumors. This means that they can spread to other areas of the body. In addition, hemangiopericytomas that have been removed surgically have a high recurrence rate.

Hemangiopericytoma

Signs and Symptoms

Hemangiopericytomas are relatively slow growing and often do not cause symptoms until they become quite large. However, once they start to compress adjacent brain tissue they may cause headaches, seizures, confusion, weakness, or visual problems.

Diagnosis

MRIs and CT scans of the brain typically reveal a contrast enhancing dural-based lesion. Cerebral angiograms show a highly vascular tumor with blood supply coming from the dura, as well as the underlying brain tissue.

Based on imaging alone, hemangiopericytomas are often mistaken for meningiomas. Subtle characteristics such as a lack of calcification seen on CT scans may help distinguish one from the other, but this is not reliable.

The only reliable way to diagnose hemangiopericytoma is to look at a specimen of the tumor under a microscope. Special stains and features of the tumor can help delineate it from a meningioma (see pathology section above).

Did I Hear Someone Say “Treatment”?

Intracranial hemangiopericytomas should be surgically resected when feasible. Unfortunately, even after complete resection, they frequently recur and/or spread to other areas of the body.

Because of their aggressive nature, patients with hemangiopericytomas should also have adjuvant radiation therapy. Radiation treatment after surgical removal of the tumor has been shown to lengthen survival and slows (but doesn’t appear to prevent) the time to recurrence.

The role of chemotherapy is less clear and is still being investigated. At this point, chemotherapy is typically used in patients where radiation and surgery have failed to control the disease.

Let’s Recap It…

Intracranial hemangiopericytomas are malignant dural-based tumors that arise from pericytes. They are highly vascular tumors that enhance on MRI and CT scans. Symptoms are variable and depend on the size and location of the tumor. Treatment is with surgical removal followed by radiation therapy. Recurrence rates are high despite optimal treatment.

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Acoustic Neuroma, and Really We Mean Vestibular Schwannoma

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Both the term “acoustic” and “neuroma” are incorrect ways of describing a tumor that arises from the 8th cranial nerve (vestibulocochlear nerve). An "acoustic neuroma" is a tumor that arises from Schwann cells that myelinate the peripheral portion of the nerve; this technically makes them “schwannomas”.

In addition, the tumor does not arise from the acoustic division of the 8th cranial nerve (ie: the portion of the nerve responsible for hearing), but instead arises most commonly from the vestibular division (ie: the balance portion of the nerve). Therefore, the appropriate medical term given to these tumors is a “vestibular schwannoma”.

These tumors are frequently caused by mutations in genes responsible for controlling cell cycle, cell morphogenesis, cell development, cell death, and cell adhesion. A well known cause of vestibular schwannomas occurs in patients with neurofibromatosis (NF) type II.

In this condition, which is responsible for about 5% of acoustic neuromas, a mutation in the NF gene on chromosome 22 causes an absent or dysfunctional protein product. This protein normally serves as a tumor suppressor; once mutated, it is no longer able to suppress tumor growth. The growth of various cells, including Schwann cells, becomes unchecked. The end result? A vestibular schwannoma.

When viewed under a pathology microscope, vestibular schwannomas are composed of different patterns of tissue. The first pattern is referred to as Antoni A; it consists of densely packed, elongated cells with nuclear free areas of cytoplasmic extensions referred to as "Verocay bodies". The second pattern is, you guessed it – Antoni B. This pattern has fewer cells and appears "looser" than the type A pattern.

These tumors are considered "benign", which means that they do not spread (metastasize) to other areas of the body. Overall, acoustic neuromas increase in size at the rate of roughly 1mm per year, but about 50% of tumors show no growth at all! Although they are not malignant tumors they can still cause symptoms.

Signs and Symptoms

Vestibular schwannomas cause local signs and symptoms. Since they arise from the 8th cranial nerve (vestibulocochlear nerve), which is responsible for hearing and balance, almost all patients present with some degree of hearing loss. In type II neurofibromatosis acoustic neuromas arising from both vestibulocochlear nerves may cause deafness. Some patients have tinnitus (ie: ear ringing), as well as a sense of vertigo.

Symptoms that are less common are a result of the tumor pressing on adjacent cranial nerves. Dysfunction of the 7th cranial nerve (facial nerve) can cause weakness of the facial muscles. If the tumor presses on the 5th cranial nerve (trigeminal nerve) it can cause face numbness; if it touches the 6th nerve (abducens nerve) diploplia (ie: double vision) may occur.

Finally, if the tumor continues to grow, it can cause compression of the brainstem. This can block the flow of cerebrospinal fluid (CSF) leading to a condition called hydrocephalus. These patients often have headaches, nausea, and vomiting secondary to increased pressure within the skull.

Diagnosis and Classification

Vestibular Schwannoma
MRI is the imaging study of choice. It will show a well encapsulated tumor that sits in the cerebellopontine angle and/or involves the internal acoustic meatus.

Audiometric analysis is important in order to document hearing loss and for monitoring treatment outcomes. The most useful test is a pure tone audiogram. Differences in hearing ability between the two ears is suspicious for an acoustic neuroma, but not specific.

Although these tumors are commonly diagnosed from characteristic MRI findings, the definitive diagnosis is made when a pathologist looks at the tumor under a microscope.

A common classification system known as the Koos grading scale is frequently used. Grade 1 tumors involve only the internal auditory canal. Grade 2 tumors extend into the cerebellopontine angle, but do not encroach on the brainstem. A grade 3 tumor fills the entire cerebellopontine angle and a grade 4 tumor displaces the brainstem and adjacent cranial nerves.

Treatment

Treatment of these tumors depends on several factors, such as how large the tumor is, and whether or not the patient has symptoms from it (ie: hearing loss, face weakness, etc). If the tumor is small it can be followed with repeat MRI to monitor for enlargement. If the tumor grows, or begins to cause symptoms, then definitive treatment should be provided.

The two most commonly used treatment modalities are surgical resection and radiation. Surgery is most useful for very large tumors or when the patient is clinically deaf. Radiation comes in two flavors: single session stereotactic radiosurgery and fractionated radiotherapy.

Stereotactic radiosurgery is a single dose of radiation delivered directly to the tumor, typically with a dose of 12 to 13 Gy. The ability to preserve useful hearing with radiosurgery ranges from 32 to 71%. For tumors less than 3 cm in diameter, the ability of radiosurgery to halt the growth of the tumor has been shown to be between 92 and 100%.

Radiation can be harmful, especially when large doses are used in one session. Inadvertent injury to the facial nerve, acoustic nerve, trigeminal nerve, and brainstem are all possible adverse events. The use of fractionated radiotherapy has been tried to decrease these risks while still delivering large doses of radiation to the tumor.

Fractionated radiotherapy spreads the total radiation dose over multiple distinct sessions. For example, a total of 40 to 58 Gy can be delivered to the tumor in 2 Gy sessions over the course of several weeks. This is more radiation delivered to the tumor compared to single session radiosurgery (13 Gy), but it is delivered over a longer time frame, which helps mitigate the risk of damaging the adjacent cranial nerves and brainstem. Hearing preservation with fractionated radiotherapy has been shown to be superior to single-session radiosurgery.

Overview

A vestibular schwannoma is a benign tumor that arises from the vestibular portion of the 8th cranial nerve. It cause hearing loss and may cause compression of adjacent cranial nerves. It is diagnosed by clinical history, audiometric studies, and MRI. Treatment consists of surgical excision, radiation therapy, or both depending on the clinical situation.

More Brain Tumors…

References and Resources

  • Ferrer M, Schulze A, Gonzalez S, et al. Neurofibromatosis type 2: molecular and clinical analyses in Argentine sporadic and familial cases. Neurosci Lett. 2010 Aug 9;480(1):49-54. Epub 2010 Jun 8.
  • Cayé-Thomasen P, Borup R, Stangerup SE, et al. Deregulated genes in sporadic vestibular schwannomas. Otol Neurotol. 2010 Feb;31(2):256-66.
  • Harner SG, Laws ER Jr. Clinical findings in patients with acoustic neurinoma. Mayo Clin Proc. 1983 Nov;58(11):721-8.
  • Bederson JB, von Ammon K, Wichmann WW, et al. Conservative treatment of patients with acoustic tumors. Neurosurgery. 1991 May;28(5):646-50; discussion 650-1.
  • Kumar V, Abbas AK, Fausto N. Robbins and Cotran Pathologic Basis of Disease. Seventh Edition. Philadelphia: Elsevier Saunders, 2004.
  • Koos WT, Day JD, Matula C, et al. Neurotopographic considerations in the microsurgical treatment of small acoustic neurinomas. J Neurosurg. 1998 Mar;88(3):506-12.

Ependymoma: Myxopapillary, Anaplastic, and Perivascular Pseudorosettes

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Ependymomas are tumors that develop from cells known as ependymal cells (duh!). Ependymal cells are a type of glial cell that line the ventricles (ie: fluid filled cavities) of the brain and central canal of the spinal cord.

Normal ependyma have cilia and microvilli on the side of the cell that faces cerebrospinal fluid (ie: the "apical" side). Cilia are hair like extensions that are believed to "beat" cerebrospinal fluid around the ventricles. Microvilli are folds in the cellular membrane that are thought to aid in the reabsorption of cerebrospinal fluid.

Unlike other epithelial cells in the body, of which ependyma are considered a subgroup, they do not rest on a basement membrane. Instead their basal surfaces (the surface not in contact with cerebrospinal fluid) intertwine with the overlying brain tissue.

Like any other cell in the body, ependymal cells can decide to turn naughty and form a tumor. Ependymomas can occur anywhere there are ependymal cells, and therefore develop in both the brain and spinal cord. Intracranial ependymomas are more common in younger age groups, whereas spinal forms are more common in older individuals. Of those that form within the confines of the skull, the most common location is in the fourth ventricle near the brainstem.

There are three "grades" of ependymoma. There are two subsets of grade one: myxopapillary and subependymomas. The second grade of ependymoma has four distinct variants. They are cellular, papillary, clear cell, and tanycytic. The third grade is also referred to as "anaplastic" ependymoma. Regardless of the grade, each type has its own distinct characteristics when viewed under the pathology microscope.

Surgical specimens of ependymomas are often "stained" by pathologists to help aid in diagnosis, and more importantly, distinguish them from other tumor types. Ependymomas stain positive for the glial fibrillary acidic protein (GFAP), as well as phosphotungstic acid hematoxylin (PTAH).

Ependymomas may have perivascular pseudorosettes, which helps support the diagnosis. Pseudorosettes may not be apparent in tumors with dense cellularity such as anaplastic ependymomas.

In addition, ependymomas can spread throughout the cerebrospinal fluid space. For example, a tumor that arises in the fourth ventricle may "drop" tumor cells down into the spinal cord forming a secondary tumor. These secondary tumors are referred to as "drop mets".

Signs and Symptoms

The signs and symptoms depend on the location of the ependymoma.

The most common symptom of intracranial ependymoma is headache associated with nausea and/or vomiting. These symptoms occur when the ependymoma blocks the flow of cerebrospinal fluid, which causes a condition known as non-communicative hydrocephalus.

You can think of non-communicative hydrocephalus as a clog in a pipe. Everything upstream of the clog starts to back up, which eventually leads to increasing pressures. When this increased pressure occurs in the ventricular system of the brain it causes worsening headaches, nausea, and vomiting. This is especially true if the ependymoma is in the fourth ventricle of the brain, which even without tumor, is an anatomically narrow "pipe" to begin with.

Additionally, if the tumor pushes on brainstem structures a patient may present with dysfunction of the nerves that go to the various muscles of the head and face. The most commonly involved nerves are the facial nerve, which can cause weakness of the face, as well as the abducens nerve, which can cause weakness of the eye.

Tumors located in the spinal cord cause weakness and sensory disturbances.

Diagnosis

Ependymoma

MRI scans can be very useful and can support (but not prove) the diagnosis of ependymoma, especially when the tumor is in a common anatomical location.

If there is a high index of suspicion for ependymoma then the entire neuro-axis, meaning the brain and entire spinal column, should be imaged using MRI. This will detect “drop” mets, which, if present, further support the diagnosis.

Diagnosis can only be officially made when a sample of tumor (either surgical or at autopsy) is seen under the pathology microscope.

Treatment

Treatment of ependymoma is with surgical resection followed by radiation therapy. Patient outcome is most effective if the entire tumor can be removed during surgery. This is known as "gross total resection". However, the extent of surgical resection should always be weighed against the risk of harming the patient, especially if the tumor has invaded vital structures like the brainstem.

Fortunately, ependymomas are very radio-sensitive, which means that they respond well to getting zapped with radiation. Chemotherapy is not typically helpful except in very young children where the effects of radiation can be devastating.

Overview

Ependymomas arise from the cells that line the ventricular system of the brain and spinal cord. There are different subtypes depending on what it looks like under the pathology microscope. Diagnosis is based on pathological analysis and characteristic MRI findings. Treatment is with surgery and radiation.

Other Diseases You Should Know About…

References and Resources

Cerebral Ateriovenous Malformations: A Disease of Eloquence

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A cerebral arteriovenous malformation is an abnormal tangle of blood vessels within the brain.

In order to understand these tangles we have to first understand normal blood flow. Blood flows from arteries to smaller arteries and then into capillary beds. In the capillary beds, gas, nutrients, and "wastes" are exchanged between the blood and adjacent body tissue. Once past the capillaries, the blood drains into successively larger veins where it eventually returns to the heart to be re-oxygenated.

In arteriovenous malformations there are no capillaries. Because of this, blood is shunted from the high pressure arterial system directly into the low pressure venous system. The "shunted" blood is unable to deliver its nutrients or oxygen to the nearby brain.

The risk of an arteriovenous malformation rupturing is relatively high because the pressure of arterial blood is "banging" into the walls of low pressure veins. The body tries to compensate for this by "arterializing" the blood vessels associated with the AVM.

The term "nidus" is often used to describe the center of the malformation. This is the point where the arterial feeding vessels meet the draining venous structures.

In addition, any brain tissue around, or within the AVM is usually gliotic (a term used to describe scarring within the brain). Macrophages are sometimes present and are usually there to "gobble up" hemosiderin (a breakdown product of blood).

Signs and Symptoms

The signs and symptoms of cerebral arteriovenous malformations are dependent on the location of the malformation.

Most patients discover they have an AVM after it bleeds into the surrounding brain tissue. Patients can present with everything from a mild headache to a severe neurological deficit depending on the location and size of the malformation.

In addition, AVMs may cause transient neurological symptoms. These transient symptoms are caused by blood being shunted away from the surrounding normal brain tissue. Again, the location of the AVM dictates what symptoms may develop (ie: weakness if near the motor strip, difficulty with speech if located near Wernicke’s or Broca’s area, balance problems if in the cerebellum, disturbances in sensation if in the parietal lobe, etc., etc.).

Patients may also present with seizures as a result of irritation of the surrounding cortex by hemosiderin (a breakdown product of blood). In fact, seizures are the second most common presenting symptom.

Interestingly, headache is an uncommon symptom of arteriovenous malformations.

Diagnosis and Classification

Cerebral Arteriovenous Malformation
Diagnosis is made with special imaging studies like CT angiography, MR angiography, and formal catheter angiography (formal angiography is the gold standard).

AVMs are characterized by an abnormal tangle of blood vessels. The tell tale sign of an AVM on an angiogram is that both arterial and venous structures are seen at the same time (normally the venous phase follows the arterial phase).

The Spetzler-Martin grading system helps guide treatment decisions. This system takes into account the size, location, and type of venous drainage (see the first reference below).

Treatment

Treatment is highly individualized. There are currently three accepted treatment strategies: surgery, radiation, and embolization.

Surgery is still the treatment of choice, especially for AVMs near the surface of the brain or in non-eloquent cortex. Surgery is also considered "definitive" therapy (ie: the AVM is removed all at once), which is ideal for lesions considered high risk for rupture. Patient’s with deep seated lesions (ie: basal ganglia, thalamus, etc.), or those located in very "eloquent" cortical areas may be better treated with radiation or embolization.

Radiation works by causing changes in the vessels of the AVM. Over the course of several months to years the vessels are "cooked" by the radiation. This effectively eliminates blood flow into the AVM. Since the effects of radiation take months to years to shut down the AVM, the patient remains at risk for rupture. In addition, side effects from radiation may be permanent in a small percentage of patients.

Embolization is usually used as an adjunct to surgical resection. During embolization, various substances are injected into the AVM. These substances deprive the AVM of its arterial blood flow. This can be very useful prior to surgery to help with intra-operative blood loss (especially for very large AVMs!). Embolization is less commonly used as a stand alone treatment.

Overview

Arteriovenous malformations are abnormal tangles of blood vessels within the brain tissue. They have no intervening capillary bed so arterial blood flows directly into dilated veins. The main risk of an arteriovenous malformation is when it ruptures and bleeds into the surrounding brain. They can cause numerous signs and symptoms depending on their location. They are diagnosed with CT angiograms, MR angiograms, or formal catheter angiograms. Treatment is with surgery, radiation, and/or embolization depending on the risk of rupture and the location of the lesion.

Other Interesting Neurovascular Diseases…

References and Resources

  • Spetzler RF, Martin NA. A proposed grading system for arteriovenous malformations. J Neurosurg. 1986 Oct;65(4):476-83.
  • Ding D, Yen CP, Xu Z, et al. Radiosurgery for patients with unruptured intracranial arteriovenous malformations. J Neurosurg. 2013 May;118(5):958-66
  • Fokas E, Henzel M, Wittig A, et al. Stereotactic radiosurgery of cerebral arteriovenous malformations: long-term follow-up in 164 patients of a single institution. J Neurol. 2013 May 28.
  • Albuquerque FC, Ducruet AF, Crowley RW, et al. Transvenous to arterial Onyx embolization. J Neurointerv Surg. 2013 Mar 6.
  • Nataraj A, Mohamed MB, Gholkar A, et al. Multimodality Treatment of Cerebral Arteriovenous Malformations. World Neurosurg. 2013 Feb 20.

Medulloblastoma: Sonic Hedgehog, Wingless, and Prognosis

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Medulloblastomas are highly malignant brain tumors. They are the most common primary malignant brain tumor, and the second most common overall brain tumor in children. They are uncommonly seen in adults. Medulloblastomas are believed to arise from the granular cell layer of the cerebellum and are part of a broader category of tumors known as primitive neuroectodermal tumors (PNETs, coolloquially called "peanuts").

The term medulloblastoma is somewhat of a misnomer because it actually comprises several distinct pathologic types. These types include classic medulloblastoma, desmoplastic/nodular medulloblastoma, large cell medulloblastoma, anaplastic medulloblastoma, and medulloblastoma with extensive nodularity.

In addition to their pathologic appearance, medulloblastomas vary in their molecular make-up. There are currently four molecular categories. They include those that belong to the sonic hedgehog gene group (SHH), the wingless gene group (WNT), and two less well understood groups known as "group three" and "group four".

The SHH group contains roughly a third of all medulloblastomas. Aberrant activation of the SHH gene is responsible for the development of all pathologic types of medulloblastomas, but is most commonly seen in anaplastic, desmoplastic, and large cell types.

The least common molecular group is the WNT group. The wingless gene signaling pathway is extremely complicated and outside the scope of this article. Suffice it to say that aberrant activation of the WNT gene can cause medulloblastoma formation, most commonly of the classic variety.

The molecular nature of group three and four is still poorly understood.

As you can see, the classification of medulloblastomas is quite complex! Medulloblastomas can be categorized both molecularly and pathologically. The table below attempts to organize the complex nature of this heterogeneous group of tumors:

Pathologic Type Molecular Type Clinical Features Outcome
Classic SHH, WNT, group 3 and group 4 Midline location, mostly in children < 10 years old, second peak in 20 to 40 year olds Better prognosis
Large cell Group 3, group 4, SHH Uncommon, similar to anaplastic Worse prognosis
Anaplastic Group 3, group 4, SHH Midline with cysts, necrosis, and bleeding within tumor Worse prognosis
Desmoplastic SHH Located in the midline in children and off midline in adults Better prognosis
Extensive nodularity SHH Off midline and nodular architecture Better prognosis

Given the malignant nature of these tumors it is not uncommon for medulloblastomas to seed other areas of the central nervous system. Tumor frequently "coats" the spinal cord. These lesions are known as "drop" metastasis and are seen in 10% to 40% of patients at the time of diagnosis.

Signs and Symptoms

Patients with medulloblastoma can present with a variety of signs and symptoms. Headaches with nausea and vomiting secondary to obstructive hydrocephalus is frequently observed. In addition, signs of brainstem dysfunction including dizziness and trouble with eye movements may occur. Cerebellar signs like ataxia and dysdiadochokinesia are also commonly seen.

Diagnosis

Medulloblastoma MRI
Characteristic imaging findings on MRI and CT scans, especially in the right age groups, can support the diagnosis. However, definitive diagnosis can only be made at the time of surgical resection by an experienced pathologist.

Treatment

Treatment is composed of surgical removal of the tumor, chemotherapy, and radiation. Surgery is always the first treatment because it decreases the disease "burden" so that radiation and chemotherapy can effectively treat any remaining tumor cells.

After surgery patients are classified as either “standard risk patients” or “poor risk patients”. Standard risk patients have complete surgical removal of their tumors and no dissemination of the disease to other areas of the central nervous system (ie: no “drop mets”). Poor risk patients have more than 1.5 cm2 of tumor left after surgery and evidence of dissemination in the cerebrospinal fluid.

Numerous chemotherapeutic medications including carboplatin, etoposide, cisplatin, cyclophosphamide, and vincristine have helped improve survival in poor risk patients. In addition, radiation therapy to the entire cranio-spinal axis has been shown to reduce recurrence rates.

Overview

Medulloblastoma is considered a malignant primitive neuroectodermal tumor. They are the second most common brain tumor in children, and the most common malignant brain tumor in children. They are rare in adults. There are several pathologic and molecular "sub-categories" of medulloblastoma; each category has different clinical features and outcome. Diagnosis is made with characteristic imaging findings in conjunction with pathologic analysis made at time of surgical resection. Treatment consists of surgery, radiation, and chemotherapy.

Related Articles

References and Resources

  • Northcott PA, Hielscher T, Dubuc A, et al. Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropathol. 2011 Aug;122(2):231-40.
  • Jones DT, Jäger N, Kool M, et al. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012 Aug 2;488(7409):100-5.
  • Northcott PA, Jones DT, Kool M, et al. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 2012 Dec;12(12):818-34.
  • Byrd T, Grossman RG, Ahmed N. Medulloblastoma-biology and microenvironment: a review. Pediatr Hematol Oncol. 2012 Sep;29(6):495-506.
  • Robertson PL, Muraszko KM, Holmes EJ, et al. Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children’s Oncology Group. J Neurosurg. 2006 Dec;105(6 Suppl):444-51.
  • Allen J, Donahue B, Mehta M, et al. A phase II study of preradiotherapy chemotherapy followed by hyperfractionated radiotherapy for newly diagnosed high-risk medulloblastoma/primitive neuroectodermal tumor: a report from the Children’s Oncology Group (CCG 9931). Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):1006-11.
  • Packer RJ, Gajjar A, Vezina G, et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol. 2006 Sep 1;24(25):4202-8.

SOCRATES: Thinking About Pain

virtualmedstudent

When I was in medical school one of the most useful mnemonics I came across was "SOCRATES". The mnemonic is designed to figure out the characteristics of someone’s pain. The characteristics of pain help the clinician develop a differential diagnosis from which testing can be ordered, and then hopefully, treatment can be given.

So what does each letter in the mnemonic SOCRATES stand for??? Let’s go letter by letter…

S   O   C   R   A   T   E   S

The first “S” stands for “site”. What body part or parts are involved? Is the pain in the leg? Is it in the abdomen? Is it a general sense of overall discomfort? The site of pain helps you fine tune your subsequent physical exam and diagnostic decision making.

The next letter is “O”, which stands for “onset”. When did the pain start? Asking about the onset of the pain is extremely important! For example, if someone has had chronic low back pain for 10 years that invokes a much lower sense of urgency than someone complaining of the sudden onset of severe belly pain or headache.

S O C R A T E S 

S – Site
O – Onset
C – Characteristics
R – Radiation
A – Associated
T – Timing
E – Exacerbating/
      Alleviating
S – Severity

“C” stands for “characteristics”. What are the characteristics of the pain? You want the patient to describe the pain in their own terms without influencing them too much. The pain may be sharp, dull, heavy, burning, etc, or a combination of descriptors.

The next letter is “R”, which represents “radiation”. I typically ask if the pain stays at the site or if it travels somewhere else in the body. For example, someone with chest pain radiating to the left arm might be experiencing a heart attack. Back pain that is associated with radiation down the leg might indicate a herniated lumbar disc that may require surgery. Back pain radiating to the abdomen could be intraabdominal pathology. Radiation of the pain is an important component to help guide your decision making.

“A” stands for associated symptoms. What other symptoms are present with the pain? For example, if the patient is complaining of belly pain do they also have nausea or vomiting? If they have a headache do they also complain of double vision or photophobia? Associated symptoms can provide a wealth of information to help you hone your differential diagnosis even more.

“T” stands for timing. When does the pain occur? Does it happen at specific times of the day, or is it constant? Does it happen during a certain movement? All of these can give you an idea of the origin for the pain.

The letter “E” represents “exacerbating” factors; grouped within this is also alleviating factors. The patient should be probed as to what makes their pain better or worse. Certain physical positions, medications, etc. may make the pain better or more unbearable. These factors can all provide historical clues about the root cause.

The final “S” stands for “severity”. In most hospitals this is formulated on a 1 to 10 scale with 10 being the most severe pain they’ve ever experienced. This can be a tricky one to gauge because many patients will describe 10 out of 10 pain when they are lying comfortably in bed; therefore, it is often necessary to ask more pointed questions and place pain in a context.

Overall, the answers obtained when using the mnemonic SOCRATES can provide a solid framework from which to order new testing and treatments.

More Good Stuff…

Glioblastoma: A Real Beast of a Tumor

virtualmedstudent

In order to understand what a glioblastoma is we have to first appreciate the different cell types that compose healthy brain tissue. Brain tissue has both neurons and glia. Neurons are the “action” cells of the brain. Glia are the “helper” cells of the brain. They ensure that neurons stay healthy.

A glioblastoma is a malignant brain tumor that arises from a specific type of glial cell known as an astrocyte. Glioblastomas are not only the most common astrocytic tumor, but they are also the most common primary brain tumor!

It is important to realize that there are less malignant tumors that arise from astrocytes (discussed in other articles). Many of these tumors have a much better prognosis, which is why it is important to distinguish glioblastoma from less malignant behaving tumors.

The first distinguishing characteristic is neovascularization. Neovascularization is a fancy medical term used to describe the proliferation of blood vessels within the tumor. As the tumor grows, it requires new vessels to feed it oxygen and nutrients; the process of neovascularization allows the tumor to obtain these essential factors so that it can continue to grow.

Interestingly, as the tumor expands, sections of it will get choked off from its own blood supply. The end result is that part(s) of the tumor actually dies. This is referred to as "necrosis", which is a common finding in glioblastoma.

One of the most distinguishing features of glioblastomas is when cancerous astrocytes "line up" and outline areas of necrosis in a process known as pseudopalisading (see image below).

Given the malignant nature of glioblastoma it is common to see many mitotic figures. Mitotic figures are cells in various states of cell division; these figures indicate a relatively rapidly growing tumor type.

Glioblastoma Pathology - Pseudopalisading

Glibolastoma is therefore characterized by the following pathological characteristics: prominent microvascular proliferation (ie: development of new blood vessels within the tumor), mitosis (ie: an indicator of cell division/growth), and necrosis (ie: areas of dead tumor); pseudopalisading necrosis is a specific form of necrosis shown in the above image that is a hallmark of glioblastomas.

Signs and Symptoms

Glioblastomas may present with any number of signs and/or symptoms depending on their location within the brain. Lesions that are located on the left side of the brain may cause problems with speech if they involve the Broca or Wernicke areas. Tumors in the areas of the brain that control motor movement may cause weakness. Additionally, tumors that arise in the frontal lobes may cause odd behavioral changes. Some patients present with seizures, and others with only a dull headache.

Diagnosis

An official diagnosis of glioblastoma can only be made when a pathologist looks at a sample of the tumor under a microscope. These samples are typically obtained by a neurosurgeon who resects or biopsies the tumor.

However, glioblastomas also have typical features seen on imaging studies such as MRI. For example, these tumors will “rim-enhance” when a contrast material such as gadolinium is infused into the patient during the scan. Rim enhancement is a result of the contrast material leaking out of all of the blood vessels present within the tumor. It is important to note that other diseases such as abscesses, lymphomas, and other infections can also cause rim-enhancement.

MRI of glioblastoma

Another useful study known as MR spectroscopy measures the relative amounts of different molecules present within the tumomr. In a glioblastoma the amount of lactate, choline, and lipid are all increased. Lactate is a marker of brain tissue that is not receiving enough oxygen, which is common in necrotic tumor areas. Choline is a molecule that is present in cell membranes. When neurons are rapidly dividing, which is what occurs in glioblastoma, the amount of choline present also increases. A different molecule known as N-acetyl aspartate (NAA) is present in mature cells. Therefore, unlike lactate and choline levels, NAA is decreased in glioblastoma because these cells are "immature" (ie: poorly differentiated).

Treatment

Treatment combines a mixture of surgery, radiation therapy, and different chemotherapeutic drugs, the most common being temozolomide (Temodar®). Surgery is only useful when a significant amount of the tumor can be removed. Despite optimal treatment the prognosis for patients with glioblastoma remains extremely poor.

It is also highly important to treat the edema that frequently surrounds the tumor. Steroids, most commonly dexamethasone (Decadron®), are used to decrease the amount of edema, which usually improves symptoms.

Patients are often started on an anti-seizure medication such as levetiracetam (Keppra®) or phenytoin (Dilantin®).

Overview

Glioblastoma is a malignant astrocytic tumor. It is the most common primary brain tumor. It has unique characteristics that distinguish it from more benign brain tumors that also arise from astrocytes. It is treated with a combination of surgery, radiation, and chemotherapy.

References and Resources