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Presented by William I. Rosenblum, MD
Material in this chapter provided by MG Hadfield, MD


Section 2: Tumors of Brain Parenchymal Cells

This chapter contains four interrelated sections. The other three sections are:

Section 1 - Tumors Arising from Coverings of the Brain, Peripheral Nerves, Blood Vessels or Blood Cells
Section 3 - Metastatic Tumors
Section 4 - Tumors of other intracranial structures

This is the second of four sections on the pathology of intracranial tumors. It is devoted entirely to neuroectodermal tumors arising from the parenchyma of the brain itself. These tumors account for approximately half of all intracranial neoplasms. We will discuss their histogenesis, classification, grading, and biological behavior. 

PRETEST: Answers will be found in the text of this section or click on link at end of questions

  1. Name 3 different malignant tumors arising from different cell types.
  2. T/F--the higher the grade the better the prognosis.
  3. What characterizes primary and secondary glioblastomas in adults?
  4. Cells of benign astroctyomas may have an elongate appearance resembling hairs and therefore are sometimes called __________ astrocytomas.
  5. Two common sites of these astrocytomas in young people are ____________________.
  6. A helpful microscopic characteristic of ependymomas is __________________.
  7. A helpful microscopic characteristic of benign, slow growing astrocytomas are ______________ fibers.
  8. In addition to anaplasia or pleopmorphism there are two so-called "secondary" signs of advanced grade of malignancy in glioma. These are ?
  9. Which of those two characteristics produces pseudopallisading?
  10. Oligodendrogliomas in adults often have deletions on which chromosomes?
  11. "Minigemistocytes" characterize some ______________ and by themselves should NOT lead to a diagnosis of _________.
  12. A highly malignant posterior fossa tumor of young people is __________________________.


Four cell types (astrocytes, oligodendroglia, ependymal cells, neurons) or their recognizable precursors give rise to virtually all tumors of primary brain tissue. However, very primitive, undifferentiated and difficult to classify tumors are sometimes encountered.

Generally speaking, the more primitive the appearance of the tumor cells, the more rapidly the tumor will grow. You will be shown the histology of the more important tumors to demonstrate the point that the neoplastic cells mimic or form caricatures of the cell of origin, either in its normal, reactive, or immature state (this is what really permits one to make correct diagnoses), and to help you understand the systems of grading  malignant brain tumors.


At present ,most pathologists use the World Health Organization system for classifying and grading tumors. In general the principles underlying WHO are similar to those employed years ago by Kernohan.

On the I-IV scale that was devised by Kernohan the highest grades indicate a greater degree of malignant change (ditto WHO). These malignant changes include increased cellularity; pleomorphism of cells, including bizarre and giant forms; hyperchromasia of nuclei; presence of immature cells; vascular proliferation and necrosis. These malignant changes are seen much more frequently in the astrocytoma series than in other neuroectodermal tumors and the discussion of anaplastic changes in astrocytomas will serve as a prototype for the others.  

Others use a three level grading system whose criteria of ascending grade are similar to the 4 point system but with obvious compression of  two grades into one. Instead of grading, some pathologists have used terms that stress resemblance of neoplastic cells to normal cells at various stages of maturity. This schema would use, in the astrocytic series, for example, the terms astrocytoma, anaplastic astrocytoma and glioblastoma multiforme to denote increasing malignancy [i.e. decreasing maturity of cells]. It is important, irrespective of the system used, that the pathologist and the clinician understand the pathologists' terms in the way that the pathologist intended with respect to prognosis.

Progress in genetic research will undoubtedly lead to further refinements in grading brain tumors. For example, glioblastomas have been found to be of two types, one with a P53 mutation and one with amplification of epidermal growth factor receptor. The former appears to arise from a more differentiated astrocytoma; the latter arises denovo (i.e., not in a preexisting tumor). 

Moreover, some oligodendrogliomas  in adults--but not in children--have been found to have deletions [ loss of heterozygosity] on chromosome 1 and 19. These having better prognosis and differential responsivity to some chemotherapeautic agents


The incidence in percentages of the more important tumors of brain parenchyma are:

  • Glioblastoma multiform 55%
  • Astrocytoma 20%
  • Ependymoma 6%
  • Oligodendroglioma 5%
  • Medulloblastoma 6%
  • Other 8%

Total: 100%

Astrocytomas are largely tumors of adults but are still the leading primary brain tumor in children. Including glioblastoma multiforme [grade 4 astrocytoma], they account for about 75% of all of tumors arising from brain parenchyma. 

These tumors can be found anywhere in the CNS, but are most frequently seen in the anterior half of the cerebrum in adults or in the posterior fossa (cerebellum and brainstem) and hypothalamus in children (juvenile type). Some of the more slowly growing astrocytomas (grade I-II) may permit survival for several years, whereas patients with glioblastoma multiform (grade IV astrocytoma) or  "anaplastic" astrocytoma (grade III) usually die within a year following surgical decompression of the tumor. 

However, since astrocytomas are virtually always invasive and display uncontrolled growth, even grade I tumors (sometimes referred to as "benign") may be truly malignant. Some grade one tumors appear to really be benign, demonstrating a sort of encapsulation by dense astrocytic tissue (?benign reactive astrocytosis) and can be "shelled out" by the neurosurgeon. These are often "pilocytic" astrocytomas--see later--and sometimes are cystic (in the cerebellum). The higher grade (III-IV) tumor is seen most frequently in middle aged adults and unfortunately accounts for 55% of all neuroectodermal tumors.

Grossly, there is poor demarcation of astrocytomas from the surrounding parenchyma. It is difficult to define where the tumor ends and normal tissue begins. All that may be seen is enlargement of the involved portion of brain and loss of distinction between grey and white matter. However, higher grade astrocytomas are usually strikingly visible since they may show marked necrosis and discoloration like the glioblastoma of the frontal lobe in the image below.

picture 1

Note that the tumor is infiltrating the corpus callosum and crossing over to the opposite side of the brain. Tumor cells will be seen microscopically, even in the areas about the tumor which appear grossly normal.

We will begin by discussing the first or slow growing group (grade I). Here, the only unusual feature encountered may be an increase in cellularity. In the image below there are too many astrocytes for normal brain tissue, but the cells themselves have the appearance of normal astrocytes with uniform, oval, vesicular nuclei and fibrillar cell processes (a "fibrous" or "fibrillary" astrocytoma).

picture 2

Another type of slow growing astrocytoma is the protoplasmic astrocytoma, in which cystic degeneration of the cytoplasm is present and the processes are less prominent in this image.

picture 3

A unique variety of this tumor is restricted to a mural nodule in a cystic cavity (cystic cerebellar astrocytoma). See image below

picture 4

In that case, it can often be cured by excision, a feat which is rarely possible with neuroectodermal tumors. In fact, this astrocytoma may be truly benign in that it does not invade surrounding tissue. In any case, it is often characterized by very elongated, neoplastic astrocytes, which are called piloid because they look like hair. Piloid astrycytomas may also be found in other areas, including the brain stem. Here, too, they have very slow growth and would be theoretically totally removable except for their location, which would make such surgery too dangerous.

The cystic cerebellar astrocytoma should not be confused with hemangioblastoma, another benign cystic tumor of the cerebellum. See section 1 of the 4 tumor sections in this chapter for information about that tumor.

Piloid astrocytomas are characterized by Rosenthal fibers which are worm-like eosinophilic bundles with irregular profiles. These are really clumped astrocytic processes with their intracellular thin filaments. Oval granular eosinophilic bodies are also seen. Both types of structure are non-specific findings indicative of long-standing pathological processes as would be the case in a benign tumor. Rosenthal fibers are also characteristic of a rare leukodystrophy--Alexander's disease--in which abnormalities have been found on the gene coding for glial fibrillary acidic protein.

The image below displays the brightly eosinophilic Rosenthal fibers and eosinophilic bodies in a slow growing astrocytoma.

picture 5

Now we will discuss the features which indicate rapid growth potential in astrocytomas, grade III-IV, respectively named by most neuropathologists as anaplastic astrocytoma and glioblastoma multiforme. The most important criterion will be the appearance of the nucleus. Atypical nuclear changes are shown in the anaplastic astrocytoma in the image below.

picture 6

There is extreme pleomorphism of these large, irregular, dark, bizarre nuclei. Often, this pleomorphism is so extreme that giant cells are seen ( arrow). However, these cells resemble both the other neoplastic astrocytes in this image and also non-neoplastic reactive  astrocytes . The points of resemblance are the homogeneous eosinophilic cytoplasm and the formation of processes--i.e.. extensions of the cytoplasm.  The degree of cellularity is also important in determining the high grade of malignancy.

Another indication of malignancy is vascular proliferation. Endothelial proliferation of a vessel in a glioblastoma multiform is seen in the image below- arrow.

picture 7

The hyperplastic vessels are very often simply very minute lumens embedded in a thick collar of fibroblasts and vascular smooth muscle. The source of the proliferating vessels or their connective tissue matrix has been much debated.

One might think that vascular hyperplasia improves the nutrition of the tumor. But, in fact, the lumens are so small that this contributes, along with the increase in total vascular length, to an increase in vascular resistance and probably to decreased blood flow in the tumor. One might even speculate that this contributes to the necrosis which is characteristic of grade 4 astrocytomas [glioblastomas] illustrated below.

picture 8

Note the irregular, necrotic, central area surrounded by a palisade of tumor cells. This is called pseudopallisading . Much of the necrosis [ which denotes the highest degree of malignancy (grade IV) ] .is presumed to be due to the fact that the tumor is growing so rapidly that it has outstripped its blood supply. There may also be a role for apoptosis.

We have just discussed and illustrated the two extremes in histological characteristics of astrocytomas: first the grade l tumor with less rapid growth potential; and then the grade III-IV (glioblastoma) with extremely rapid growth. Between these extremes is the grade II astrocytoma, with intermediate cellularity, pleomorphism and anaplasia. Grade II tumors have an intermediate growth potential, but like grade I tumors they can change during their life history into much more rapidly growing grade III-IV tumors.


The ependymomas are predominantly tumors of childhood and adolescence and account for 6% of all neuroectodermal tumors. Survival usually does not exceed a few years. They arise most frequently in the fourth ventricle and may cause hydrocephalus by blocking off the normal flow of CSF. However, they can occur anywhere in relation to the ventricular system or central canal and are the most common glioma in the spinal cord and filum terminale. In the spinal cord, they are somewhat well circumscribed and can sometimes be "shelled out" surgically.

picture 9

Microscopically, they are composed of elongated cells that have been designated as "ice cream cone," "tadpole," or "carrot" cells because of their tapering shape (image above). The nucleus is located at the large end and mimics the basal location of the nuclei in normal ependymal cells. 

These features are seen best in the cells that are arranged in the true rosettes or "miniature ventricles" so clearly seen in the figure. However small "nuclear free zones" as seen in the lower right corner of the figure above are far more frequent than true rosettes and should help the pathologist  toward the diagnosis of ependymoma. These "nuclear free zones" are thought to be a consequence of the tendency of the tumor cells to line up around blood vessels to form "pseudorosettes".  However [image below] in these cases there is abundant cytoplasm between the tumor cell nuclei and the blood vessel. So much so, that tangential cuts through these structure may show large , pink [eosinophilic] fields without nuclei [the  commonly found "nuclear fee zones".

picture 10

Very anaplastic examples (grade III-IV, ependymoblastomas) are infrequently encountered.


A tumor that is related to ependymomas is the choroid plexus papilloma. It is benign although choroid plexus carcinomas do exist.

picture 11


A tumor formerly  thought to be related to ependymoma or choroid plexus is the colloid cyst of the third ventricle (image below). However electronmicroscopy has shown that in some specimens the cyst lining most closely resembles bronchial mucosa which suggests a derivation from displaced bronchial cleft tissue. In any case , this benign tumor can kill if it obstructs the foramina through which CSF passes from lateral to third ventricle. This will suddenly raise intracranial pressure causing severe headache and possible death. Since the tumor is often on a stalk, it may intermittently obstruct the passage of CSF, depending upon the  exposition of the patients head. Therefore positional, severe headache is an important clue to this potentially life threatening but curable condition.

picture 12


These tumors are usually found in the cerebral hemispheres of middle aged adults and comprise about 5% of neuroectodermal tumors. They grow fairly slowly and there is a mean 5-year survival rate. The tumors may appear more circumscribed than astrocytomas.

picture 13

The cells are very uniform and have been described as "fried egg" or "fish eye" cells because of a round, central nucleus surrounded by a clear space or halo (unstained cytoplasm, image above). This appearance depends upon fixation or upon delayed fixation and will not be seen in immediately frozen tissue. Note that the cell membranes are very distinct, giving a honeycomb appearance to the sheets of tumor cells. The tumor cells often occur in nests compartmentalized by delicate blood vessels and their associated connective tissue ["chicken wire"] [Image below]

picture 14


This tumor also has a tendency to calcify which is sometimes helpful in its radiological diagnosis. Malignant examples (grade III-IV, oligodendroblastomas) are sometimes encountered. As  noted earlier some oligodendrogliomas are characterized by deletions in chromosomes 1 and 19. Some oligodendrogliomas contain small cells that have pink cytoplasm and look like small reactive astrocytes of the gemistocytic variety. This has led to including these tumors in the group of mixed astro-oligodendglioma. Such mixed tumors do exist and the prognosis is the more ominous one associated with malignant astrocytomas. However in such mixed tumors the astrocytic component is not restricted merely to small, so-called, "minigemistocytes". When only the latter are present the tumors are now known to behave like oligodendrogliomas and are now simply called oligodendrogliomas.


All of the previous tumors that we have discussed have been of glial origin (gliomas). Tumors of neuronal origin are rare and the only important intracranial tumor of this group is the medulloblastoma (neuroblastoma). The term medulloblastoma is a misnomer, since a medulloblast has never been isolated, but the name is too well entrenched to be eradicated. 

Most workers think that these tumors arise from identical cells in one of two sites. First, from migrating neuroblasts which have become arrested in the roof of the fourth ventricle (anterior medullary vellum). This would account for the midline location of many of the tumors. Second, from the external granular layer of the cerebellum. The migrating cells form this layer in the immature cerebellum before entering the deep cerebellar cortex (granular layer). The external granular layer disappears (through inward migration) by the second year of life. Because of its origin from immature cells, it is not surprising that the majority of medulloblastomas are seen during the first decade of life. However, there is another peak in young adulthood. These tend to be more laterally placed and have a better prognosis. The fact that some medulloblastomas may simultaneously differentiate along astrocytic lines is another reason that some pathologists retain the name "medulloblastoma."

picture 15

Since the cells of origin are destined for the cerebellum, medulloblastomas are posterior fossa tumors usually located in the midline of the cerebellum as indicated above. The tumor fills the fourth ventricle (image above, arrows) and characteristically invades the subarachnoid space and seeds up and down the cerebrospinal fluid pathway. This accounts for a generally poor prognosis, though survival is vastly improved following heavy, total neuraxis irradiation. In the image below a huge mass of tumor cells is seen in the subarachnoid space (arrows) and down the spinal cord.

picture 16

These tumor cells occur in highly cellular sheets which resemble the small, round, lymphocyte-like granular neurons of the normal cerebellar cortex (image below).

picture 17


Last Updated 15-May-2007