chemotherapy

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.

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References and Resources

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.

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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.