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The Supratentorial Mass in an Adult

  • Cynthia T. Welsh
  • M. Timothy Smith
Chapter

Abstract

36-year-old male Pain in right eye CT of orbits demonstrated left frontal abnormality Normal neurologic exam

Keywords

Progressive Multifocal Leukoencephalopathy Astrocytic Tumor Glial Tumor Oligodendroglial Tumor Choroid Plexus Papilloma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Case 3AA 36-Year-Old Male with an Incidental Frontal Lesion

  • Cynthia T. Welsh

Clinical History

  • 36-year-old male

  • Pain in right eye

  • CT of orbits demonstrated left frontal abnormality

  • Normal neurologic exam

What Is Your Diagnosis?

Figure Discussion
Scans

The coronal MRI pre- and postcontrast show no change (enhancement) in the left frontal tumor, just in vasculature next to the tumor, so only the postcontrast scan is shown. The tumor is much more apparent on the axial T2 scan, and the FLAIR sequence shows this is not just fluid, it is increased cellularity (Figs. 3A.13A.3).

Pathology
Uneven smearing, mild increases in the number of cells with clustering of those cells, a change in the neurofibrillary background (looser than normal), and abnormal nuclei without visible individual cytoplasm/processes (bare nuclei) are all indications that not only is the tissue abnormal but also neoplastic. The processes are consistent with an astrocytic origin for the tumor cells. The cells are traveling along white tracts (Figs. 3A.43A.8).
Fig. 3A.1

Axial MRI T2 FLAIR – left frontal lesion which appears to involve gray and white matters

Fig. 3A.2

Coronal MRI T1 postcontrast – very little, if any, enhancement

Fig. 3A.3

Axial MRI T2 – left frontal lesion which appears to involve gray and white matters

Fig. 3A.4

Smear (H&E low magnification) – tissue clumping

Fig. 3A.5

Smear (H&E high magnification) – gemistocyte

Fig. 3A.6

Smear (H&E high magnification) – “bare,” irregular, hyperchromatic nucleus

Fig. 3A.7

Frozen section (H&E high magnification) – “bare” irregular hyperchromatic nuclei

Fig. 3A.8

Frozen section (H&E high magnification) – increased ­cellularity with cell clusters infiltrating white matter tracts

Diagnosis: Low-Grade Astrocytoma

Low-grade tumors in adults tend to be associated with presenting seizure or long standing headache more often than high-grade tumors, or they may be an incidental finding as in this case. Tumors in adults tend to be supratentorial, and low-grade tumors are no exception. The most common low-grade tumors in adults, diffuse (fibrillary) astrocytomas (followed by the less common oligodendrogliomas), are infiltrative on MRI scans, bright on T2 and FLAIR sequences, and do not enhance. This is in contrast to a number of the other low-grade gliomas (pleomorphic ­xanthoastrocytoma (PXA), ependymoma, pilocytic astrocytomas (PA), and ­ganglion cell tumors) which are distinct from surrounding neural tissue (Table 3A.1). Low-grade astrocytomas other than PA do not typically enhance or have necrosis. They often have cysts and are generally seen in younger patients. Glial tumors that infiltrate, such as fibrillary astrocytomas and oligodendrogliomas, may track along white matter tracts giving a thickened ­corpus callosum and/or internal capsule.
Table 3A.1

Primary brain tumor configurations. Tumor growth patterns

Diffuse

Localized

Fibrillary astrocytoma

PXA

Oligodendroglioma

Pilocytic astrocytoma

Lymphoma

Ganglion cell tumor

 

Ependymoma

 

Choroid plexus tumor

 

Subependymoma

 

DNET

 

Hemangioblastoma

 

Neurocytoma

 

SEGA

Intraoperatively, the age, clinical presentation, and fact that the tumor does not enhance should influence you heavily in favor of a low-grade process. White matter-based lesions tend to be astrocytic. The cortical based ones are often oligodendroglial, or dysembryoplastic neuroepithelial tumor (DNET). Or, particularly if grossly cystic, they may be PXA, ganglioglioma, or even pilocytic.

The low-grade astrocytoma will often be of low cellularity with the chief histologic differential being reactive gliosis or other low-grade tumor. The tissue will not smear as evenly as normal brain; clumping may be very similar to that of reactive brain. The neuroglial background will be abnormal. Neoplastic astrocytes have fewer, short, stubby processes than reactive astrocytes, or the processes are not apparent (“bare nuclei”). The cells tend to cluster, be less uniform, and/or be seen in numbers beyond the realms of just reactive (almost back to back). Nuclei are larger and more irregular than normal, or those seen in low-grade oligodendrogliomas. Some reactive lesions can actually show more nuclear atypia than low-grade neoplasms, but the cells also have lots of cytoplasm. Very little, or no, inflammation (especially ­neutrophils or macrophages) is usually seen. No high-grade features are present.

Differential Diagnosis: Gliosis

Gliosis (astrocytosis) is common to most processes in the brain. Reactive astrocytes make the brain appear too cellular and can easily be mistaken for tumor astrocytes. They make the tissue smear less evenly than normal brain, in a pattern very similar to low-grade tumor. The individual astrocytes may vary from a display of long, thin processes (Fig. 3A.9), which radiate evenly around the entire circumference of the nucleus to shorter, thicker, and fewer processes, which sometimes approach the changes seen in neoplasia. Early in the process, the cytoplasm becomes prominent next to the nucleus (gemistocytic change); later this perinuclear cytoplasm shrinks, but the cytoplasm in general remains more prominent than normal. The nuclear changes also show a large range, varying from small and oval to large, hyperchromatic, and irregular (once again simulating neoplasia). Nucleoli can become prominent in either reactive or neoplastic astrocytes. More reliable evidence (Table 3A.2) for the process being reactive includes the relatively even spacing of the cells (Fig. 3A.10), and the background (if present) of other cells such as macrophages, microglia, neutrophils, and (less useful) lymphocytes. Vessels are reactive (Fig. 3A.11) also as opposed to the complex vascular changes seen in tumors. Gliosis is seen with infections, demyelinating processes (such as PML and MS), and vascular lesions (such as infarct). It is also seen adjacent to metastases and within/nearby ­oligodendrogliomas, so the fact that you see no tumor in the material at which you are presently looking, does not mean there is no tumor in the patient (a caveat to mention to the neurosurgeon).
Fig. 3A.9

Smear – gliosis – long thin processes on astrocytes

Fig. 3A.10

Histology – gliosis – even spacing of astrocytes

Fig. 3A.11

Histology – gliosis – reactive blood vessels

Table 3A.2

Reactive brain versus neoplasm

 

Gliosis

Diffuse astrocytoma

Radiologic findings

 

Loss of gray–white junction

Distribution of cells

Even

Irregular, clusters

Bare nuclei

No

Yes

Microcysts

Rare

Common

Macrophages

Depends on process

Rare

Other inflammatory cells

Depends on process

Rare

Satellitosis

No

Yes

Cell processes

Thin, long, uniform

Short, fat

More Rosenthal fibers than cells?

Frequent

Seldom

Calcification

No

Maybe

Vessels

Enlarged endothelial

Increased numbers cells

Differential Diagnosis: Oligodendroglioma

Oligodendroglioma usually enters the differential when there are too many cells and they are not just reactive astrocytes or inflammatory cells. Around the edges of the tumor, where a few cells infiltrate the brain, is frequently the most difficult place to tell that the tumor is oligodendroglial. There are almost always reactive astrocytes present because of the brain infiltration. These also add to the cellularity, and may make the disease process appear to be astrocytic. Within the center of the low-grade oligodendroglioma there are evenly placed small cells (Table 3A.3) and small capillaries (Fig. 3A.12) around nests of cells (“chicken wire fencing”) on tissue sections. The “haloes or fried eggs” so promptly diagnostic on permanent sections, are mostly an artifact of fixation, and usually won’t be seen well on frozen sections. On smears the cells will have only a small rim of cytoplasm (Fig. 3A.13), if any, without the long processes of an astrocyte (often the cytoplasm is stripped off leaving bare nuclei). Nuclei having a large enough rim may be termed “mini- or microgemistocytes.” The nuclei tend to be rounder, less irregular, and less pleomorphic than those of astro­cytomas. Oligodendrogliomas commonly have calcifications (Fig. 3A.14), but these can be confused with corpora amylacea, bone dust, or other debris, and are not exclusive to oligodendrogliomas. Microcysts (Fig. 3A.15) are typical in many low-grade tumors, especially oligodendrogliomas. Satellitosis of tumor cells around neurons is more common than in astrocytic tumors. A few mitoses do not make an oligodendroglial tumor high grade, and hypercellular nodules are common in oligodendroglial tumors, so they shouldn’t make you think high grade either.
Fig. 3A.12

Smear – oligodendroglioma – fine capillaries small nuclei

Fig. 3A.13

Smear – oligodendroglioma – sometimes a small rim of cytoplasm

Fig. 3A.14

Smear – oligodendroglioma – microcalcification

Fig. 3A.15

Histology – oligodendroglioma – microcysts

Table 3A.3

Cell distribution in brain

Process

Cell spacing

Normal/reactive astrocytes

Even

Diffuse astrocytoma

Clusters

Normal oligodendrocytes

Clusters, rows

Oligodendroglioma

Even spacing usually

Occasionally cords

Differential Diagnosis: Other Primary Low-Grade Glial Tumor

The appearance in these slides doesn’t lend itself to as wide a differential as is actually possible with low-grade diffuse astrocytoma. If the morphology were gemistocytic, then you would want to know if the tumor were near the ventricle in a patient with Tuberous Sclerosis (high likelihood of a subependymal giant cell astrocytoma (SEGA)), or if the MRI showed a cyst with a peripheral nodule (possible PXA). SEGA (Fig. 3A.16) will have cells which appear somewhat neuronal admixed with the large astrocytic appearing cells. PXA have lipidized cells (Fig. 3A.17) and tend toward a degree of pleomorphism outside the usual bounds of ­gemistocytic astrocytomas. They are localized rather than infiltrative like all fibrillary tumors are (whether gemistocytic or not). Particularly, in certain locations where piloid astrocytes are common, the differential may include pilocytic astrocytoma. In a child with a posterior fossa astrocytic tumor, it will more often be pilocytic, but can be fibrillary (Fig. 3A.18) and yet appear spindled. The nuclei of pilocytic tumors are more spindled, and less irregular or hyperchromatic for the most part. The processes are hairlike (“piloid”) or bipolar. Rosenthal fibers may be focal. Eosinophilic granular bodies are usually frequent. If large neurons are present, the question arises whether the neurons are part of normal gray matter infiltrated by tumor, or if the neurons are also neoplastic (ganglioglioma). Neoplastic neurons lack the organization of normal cortex rows and columns, they are often too large and/or too many for the location, and may be binucleate.
Fig. 3A.16

Histology – SEGA – large cells with variable cytoplasm; some eosniophilic, others with Nissl substance

Fig. 3A.17

Histology – PXA – large cells with bizarre morphology and vacuoles

Fig. 3A.18

Histology – fibrillary astrocytoma – a suggestion of bipolar morphology

Differential Diagnosis: PCNSL

When cellularity is higher than seen in this case, or the nuclei are less angular, a primary lymphoma (Fig. 3A.19) may enter the differential diagnosis, particularly in an immunocompromised patient or someone elderly. A tumor location closer to ventricle than central white matter favors lymphoma. Perivascular cuffs of cells are seen best near the edges of the tumor. Primary CNS lymphomas are almost always large B-cell lymphomas (PCNSBL) with large vesicular nuclei, and usually fairly prominent nucleoli (which you will recognize as having a similar lymphoid character to the systemic large B-cell lymphomas with which you are familiar). Single cell death, which is uncommon in most glial tumors, is prominent in lymphomas. When the specimen is from the center of the tumor, the differential diagnosis is much more likely to be between lymphoma and some other high-grade tumor.
Fig. 3A.19

Histology – pcnsbl – infiltrating, monotonous, fairly small nuclei

Case 3BA 40-Year-Old Female with New Onset Seizures

  • Cynthia T. Welsh

Clinical History

  • 40-year-old female

  • New onset seizures

  • Right arm numbness

  • History of pituitary adenoma (on medical treatment)

  • Exam:
    • Decreased sensation right arm

What Is Your Diagnosis?

Figure Discussion
Scans

The tumor is dark on T1, and does not enhance (scan not included). It is more apparent on T2, and the cortical involvement is demonstrated particularly well on the FLAIR sequence (Figs. 3B.13B.3).

Pathology
Microcysts can break apart on smears done with too much pressure, but some of these are intact. The vascular pattern is predominantly that of increased capillary size vessels. Cytoplasmic clearing is seen on the touch preparation and a thin rim of cytoplasm on one smear. Calcifications are present. Nuclei are small and mostly round and seem evenly spaced on the low power histology. These are all findings consistent with an oligodendroglial origin for the tumor (Figs. 3B.43B.9).
Fig. 3B.1

Axial MRI T1 precontrast – gray–white interface disruption in the left frontal lobe

Fig. 3B.2

Axial MRI T2 – cortical involvement apparent

Fig. 3B.3

Axial MRI T2 FLAIR – cortical involvement apparent

Fig. 3B.4

Smear (H&E low magnification) – microcysts, small nuclei, capillaries

Fig. 3B.5

Smear (H&E low magnification) – small nuclei, background astrocytes, capillaries

Fig. 3B.6

Touch preparation (H&E high magnification) – astrocyte surrounded by cells with cytoplasmic clearing

Fig. 3B.7

Smear (H&E high magnification) – small round nuclei, fine chromatin, and chromocenters

Fig. 3B.8

Frozen (H&E low magnification) – small nuclei, evenly spaced, perinuclear clearing

Fig. 3B.9

Frozen (H&E high magnification) – small nuclei, evenly scattered, microcalcifications, reactive astrocyte

Diagnosis: Oligodendroglioma

The low-grade oligodendroglioma centrally has evenly spaced small cells and small capillaries around nests of cells (“chicken wire fencing”) on tissue sections. The “haloes or fried eggs” that we all equate with oligodendrogliomas, are mostly an artifact of fixation, and usually won’t be well seen on frozen sections. On smears the cells will have only a small rim of cytoplasm, if any, without the long processes of an astrocyte (often the cytoplasm is stripped off leaving bare nuclei). The histologic differential diagnosis includes many other small cell processes, but the clinical history and radiologic findings sharply limit the real differential diagnosis. Patients with low-grade oligodendrogliomas are often young (although not always) and present with seizures. The cortical spread of the tumor that presumably accounts for the seizures can be seen on scans and should be a clue as to differential. Nuclei having a large enough rim may be termed “mini- or microgemistocytes.” Oligodendroglial nuclei tend to be rounder, less irregular, and less pleomorphic than those of astrocytomas. Oligodendrogliomas commonly have microcalcifications (and larger calcifications may be seen on scans), but these can be confused with corpora amylacea, bone dust, or other debris, and can also be seen in other tumors (Table 3B.1). Microcysts are typical in many low-grade tumors, especially but not exclusively, oligodendroglial tumors (Table 3B.2). Satellitosis of tumor cells around neurons is so frequent, that the tumors often seem on scans to be cortically based, although once again oligodendrogliomas are not the only tumors to invade cortex (fibrillary astrocytomas do less commonly). Oligodendrogliomas commonly have nodules which are rather abruptly more ­cellular; these do not denote a tendency to higher grade. If no high-grade features are seen, the intraoperative diagnosis is most often “low-grade glioma.” In sufficient numbers, mitoses would prompt you to say “high-grade glioma” intraoperatively in an astrocytoma, and complex microvascular changes may also. This is not true of oligodendrogliomas. So the nuclear details on smears (and sections), the vessels (are they all capillaries?), and the spacing of the cells (Table 3B.3) need to be considered carefully before upgrading the tumor.
Table 3B.1

Microcalcifications

Normal

 
 

Meninges

 

Pineal

 

Choroid plexus

Non-neoplastic conditions

 
 

Especially injury

 

Particularly in children

Tumors

 
 

Oligodendroglioma – common in cortex

 

Neurocytoma – common

 

SEGA – common

 

Astroblastoma

 

Astrocytoma – occasional

 

Ganglion cell tumors

 

Ependymoma (particularlyclear cell subtype)

 

Pilocytic – occasional

Table 3B.2

Microcystic (all tumors!)

Meningioma

Pilocytic astrocytoma

Pilomyxoid astrocytoma

Oligodendroglioma

DNET

Ganglion cell tumors

Craniopharyngioma

PNST

Ependymoma

Subependymoma

Teratoma

Astroblastoma

Fibrillary astrocytoma – rarely

Table 3B.3

Cell distribution in brain

Process

Cell Spacing

Normal/reactive astrocytes

Even

Diffuse astrocytoma

Clusters

Normal oligodendrocytes

Clusters, rows

Oligodendroglioma

Even spacing usually

 

Occasionally cords/ribbons

Differential Diagnosis: Gliosis (Astrocytosis)

Gliosis often enters the differential diagnosis for oligodendrogliomas because of the reactive astrocytes incited by the tumor cells infiltrating through brain. It is also seen with infections, demyelinating processes (such as PML and MS), and vascular lesions (such as infarct). The vacuolated cytoplasm of macrophages seen in many of these lesions can be mistaken for oligodendrocytes. Gliosis makes the tissue smear less evenly than normal brain, and more like low-grade tumor. It will make the tissue appear hypercellular. The individual astrocytes may vary from a display of long, thin processes, which radiate evenly around the entire circumference of the nucleus (Fig. 3B.10) to shorter, thicker, and fewer processes, which sometimes approach the changes seen in neoplasia. Early in the process, the cytoplasm becomes prominent next to the nucleus (gemistocytic change); later this perinuclear cytoplasm shrinks, but the cytoplasm in general remains more prominent than normal. The nuclear changes also show a large range, varying from small and oval to large, hyperchromatic, and irregular (once again simulating neoplasia). Nucleoli can become prominent in either reactive or neoplastic astrocytes. The nuclei are more angular than those of the low-grade oligodendroglioma. Evidence for the process being reactive includes the relatively even spacing of the astrocytes (Fig. 3B.11), and the background (if present) of other cells such as macrophages, microglia, neutrophils, and (less useful) lymphocytes. Vessels will be reactive in non-­neoplastic gliosis (Fig. 3B.12) rather than show complex microvascular changes or the increased capillary architecture of an oligodendroglioma. The reactive astrocytes in an oligodendroglioma should not lead you to call the tumor an oligoastrocytoma.
Fig. 3B.10

Smear – gliosis – long thin processes on clumps of astrocytes

Fig. 3B.11

Histology – gliosis – even spacing of astrocytes and processes accentuated by ice crystal artifact

Fig. 3B.12

Histology – gliosis – reactive blood vessels in a sea of macrophages

Differential Diagnosis: Normal White Matter

Normal oligodendrocytes appear in gray matter, are very numerous in white matter, and have a tendency toward clusters (Fig. 3B.13) and rows of cells that should not be confused with oligodendroglioma. We talk about using astrocyte spacing when we are comparing reactive with neoplastic; this does not apply to oligodendrocytes which normally form rows and groups. The first specimen from the neurosurgeon is actually often normal/reactive tissue on the way to the tumor.
Fig. 3B.13

Histology – normal white matter – clusters of oligodendrocytes

Differential Diagnosis: Low-Grade Diffuse Astrocytoma

Low-grade astrocytoma will often be of low cellularity and can be similar in appearance to the infiltrative edges of oligodendrogliomas. Unlike reactive astrocytes which remain fairly evenly spaced, or oligodendrogliomas which from low power also give you the impression of even spacing, neoplastic astrocytes tend to cluster (Fig. 3B.14). The nuclei are larger, and more hyperchromatic and irregular (Fig. 3B.15) than low-grade oligodendroglial nuclei. Astrocytic cells have processes which may show up well on frozen sections due to ice crystal artifact, but will definitely be very obvious on cytologic preparations (Fig. 3B.16). Astrocytomas have microcysts, microcalcifications, and secondary structures like satellitosis less often than oligodendrogliomas, but they do still happen. Oligodendrogliomas are infiltrative tumors which incite an astrocytic reaction (gliosis). Do not confuse these astrocytes with neoplastic astrocytes and call the tumor an oligoastrocytoma. When no high-grade features are present, the intraoperative diagnosis is often “low-grade glioma” which is specific enough at that point.
Fig. 3B.14

Histology – low-grade diffuse astrocytoma – clusters of cells

Fig. 3B.15

Histology – low-grade diffuse astrocytoma – large dark irregular “bare” nuclei

Fig. 3B.16

Smear – low-grade diffuse astrocytoma – few, short, broad processes

Differential Diagnosis: Extraventricular Neurocytoma

Many neurocytomas are intraventricular, which should make you think of them in the differential (if you know the tumor location), but particularly when extraventricular, the differential diagnosis includes oligodendrogliomas. Neurocytomas can have haloes, microcalcifications, and small fairly round nuclei (Fig. 3B.17) like oligodendrogliomas. In comparison to oligodendroglioma, there is extra neuropil in neurocytomas and the tendency to make neuronal rosettes. The nuclei tend to be more uniformly round. Smears show the rosettes and clumps of neuropil, and you don’t have the rim of cytoplasm that careful preparations from oligodendrogliomas can demonstrate. Because this tumor is localized rather than infiltrative, it doesn’t have astrocytes within it, and is possible to totally remove, unlike oligodendrogliomas.
Fig. 3B.17

Histology – neurocytoma – cleared cytoplasm and microcalcifications

Differential Diagnosis: DNET

Dysembryoplastic neuroepithelial tumors (DNETs) have oligodendroglial appearing cells and microcysts (Fig. 3B.18). The neurons seen are not just trapped cortical neurons like in oligodendrogliomas. DNET is potentially totally removable with no recurrence, so it can be important to differentiate from oligodendroglioma (which is neither of the above) during surgery. The patients are generally young and present with seizures also. The scans may show a pattern which you may also see on microscopy, of multiple nodules of microcystic change. The brain between the nodules will generally be less cellular than in other tumors.
Fig. 3B.18

Histology – DNET – oligodendroglial-like cells, ganglion cells, and microcysts

Differential Diagnosis: PCNSL

Primary CNS lymphoma (PCNSL) usually has a periventricular location as opposed to oligodendroglioma which is ­cortical/subcortical, so knowing the location on scans helps you start differentiating between the two of them. There are sheets of back-to-back cells in the middle of both oligodendrogliomas and in PCNSL (Fig. 3B.19). Neither tumor cell usually has much cytoplasm in evidence. The cells are generally much larger in lymphomas (although they can appear deceivingly small in frozen sections), and nucleoli are usually prominent unlike oligodendroglioma. Low-grade oligodendroglioma does not have the necrosis that is typical for lymphoma. Lymphoma is not a surgical neoplasm, so intraoperative diagnosis allows for a shorter, less extensive procedure.
Fig. 3B.19

Histology – PCNSBL – infiltrating, monotonous, fairly small appearing cells

Differential Diagnosis: Pilocytic

Particularly in the cerebellum, pilocytic astrocytomas have cells within them that are oligodendroglial-like (Fig. 3B.20). In a child, in the posterior fossa, a pilocytic tumor would be much more common that an oligodendroglioma. Determination intraoperatively of the pilocytic nature of the tumor reassures the surgeon that gross total excision is a reasonable goal. Looking for the biphasic nature, hair-like “piloid” cells, and Rosenthal fibers helps to make the diagnosis and reassures the neurosurgeon that as complete an excision as possible is the correct course of action.
Fig. 3B.20

Smear – pilocytic – small round monotonous oligodendroglial-like nuclei

Differential Diagnosis: Ependymoma (Especially Clear Cell)

Clear cell ependymomas (Fig. 3B.21) have clear cells very similar to oligodendrogliomas and have microcalcifications like oligodendrogliomas. They tend more than other ependymomas to occur outside the ventricular system, but should appear more well circumscribed than oligodendrogliomas on scans. On either smears or frozen sections perivascular pseudorosettes (Fig. 3B.22) will be seen, but may be focal requiring extensive sampling. The nuclei of ependymal cells are generally more oval than oligodendrocytes, and the cytoplasm greater in volume and more eccentric (possibly actual processes). If the ependymal nature can be determined intraoperatively, the surgeon will be more likely to try to completely excise the tumor.
Fig. 3B.21

Histology – ependymoma – small nuclei with a suggestion of cytoplasmic clearing and increased capillaries

Fig. 3B.22

Histology – ependymoma – clearing around the small nuclei, but perivascular pseudorosettes

Differential Diagnosis: Small Cell Anaplastic

The small cell variant of fibrillary astrocytoma (Fig. 3B.23) has small cells with minimal cytoplasm and perinuclear haloes. The nuclei are often more oval than the typical elongate, irregular nuclei of astrocytomas. There is a brisker mitotic rate than in low-grade oligodendroglioma. The issue here will be more for eventual determination of the correct category for the tumor and subsequent type of appropriate molecular studies.
Fig. 3B.23

Histology – small cell anaplastic astrocytoma – irregular nuclei, cleared cytoplasm, microcalcification

Differential Diagnosis: Glioblastoma

Pure oligodendroglioma with mitoses, complex microvascular changes, and necrosis is a WHO grade III tumor. A mixture of astrocytes with the oligodendrocytes makes the tumor glioblastoma with an oligodendroglial component, WHO grade IV, because the astrocytes are worse actors. The small cell variant of GBM (Fig. 3B.24) most closely resembles high-grade oligodendroglioma because the cells are smaller and packed closely together than typical for glioblastoma. Necrosis is often very focal. The diagnosis intraoperatively will be “high-grade glioma” and the final correct definition left for permanent sections.
Fig. 3B.24

Histology – small cell glioblastoma – frozen artifact distorting the tissue, irregular pleomorphic nuclei, many mitoses

Cautions

  • Haloes are not always seen in oligodendrogliomas (so you will miss the diagnosis if you insist on seeing this feature).

  • Oligodendrogliomas are not the only tumor with haloes (and don’t forget normal cells can have haloes).

  • Oligodendrogliomas are not automatically high grade based on mitoses and/or complex microvascular changes.

Case 3C A 74-Year-Old Female with Seizure, and Hemiparesis

  • Cynthia T. Welsh

Clinical History

  • 74-year-old female

  • Seizure, altered mental status

  • Headache, left hemiparesis

  • History ovarian cancer

  • Exam:
    • Left facial droop

    • Left upgoing toe

    • Left side decreased sensation

What Is Your Diagnosis?

Figure Discussion
Scans

The tumor enhances in approximately a ring with extra strands of contrast. The infiltration of tumor cells into brain outside of the main “mass” is illustrated by the bright signal on the FLAIR sequence (Figs. 3C.13C.3).

Pathology
The increased cellularity and numerous abnormal nuclei, most without individual cytoplasm (bare nuclei) are seen on both the smears and frozen section. The higher grade features of mitoses, complex microvasculature with increased vascular wall cellularity, and necrosis are also seen on both cytology and histology. The processes are consistent with an astrocytic neoplasm (Figs. 3C.43C.9).
Fig. 3C.1

Axial MRI T2 – bright CSF and right hemisphere tumor

Fig. 3C.2

Axial MRI T1 postcontrast – ring enhancement

Fig. 3C.3

Axial MRI T2 FLAIR – dark CSF, but tumor remains bright

Fig. 3C.4

Smear (H&E high magnification) – large, hyperchromatic, irregular nuclei

Fig. 3C.5

Smear (H&E high magnification) – complex microvascular change

Fig. 3C.6

Smear (H&E high magnification) – necrosis

Fig. 3C.7

Smear (H&E high magnification) – mitosis

Fig. 3C.8

Frozen section (H&E low magnification) – complex microvascular change

Fig. 3C.9

Frozen section (H&E low magnification) – necrosis

Diagnosis: High-Grade Glioma

High-grade astrocytic tumors in adults can be seen at all ages, but tend to be more common with increasing age. The majority, as with most adult tumors, are supratentorial. On MRI scans, high-grade tumors enhance (Table 3C.1) and glioblastomas (GBM) usually enhance around necrosis (ring-enhancement). The differential diagnosis for the usual “ring-enhancing” lesion in an elderly adult consists of glioblastoma, metastasis, abscess, and lymphoma. During the intraoperative consultation, glial tumors are often designated as low or high-grade glioma (with grades 3 and 4 considered together) and astrocytic lumped with oligodendroglial as “glioma.” Usually this information is enough for the neurosurgeon, although clinical research protocols may require more, such as being able to say “glioblastoma”; this may necessitate additional tissue. As glial tumors increase in grade, nuclear differences between astrocytic and oligodendroglial tumors start to blur. Vessels become more alike also. A higher grade is usually heralded microscopically by increased cellularity and mitoses first. Generally, the complex microvascular changes and necrosis are later than (in addition to) the mitoses. The mitoses, vascular changes, and necrosis can all be seen on both tissue sections and smears. If enough of the high-grade features (including necrosis) are present, and the tumor is definitely at least partly astrocytic then you can say it is a glioblastoma (we no longer use the term “multiforme”). Pseudopalisading (Table 3C.2) around the necrosis is instantly recognizable but is not necessary for the diagnosis. There are many variants of glioblastoma such as giant cell, spindle cell, and small cell (which can be mixtures), and therefore many malignant metastatic tumors enter the histologic differential. They all have astrocytic differentiation, which may show better on smears, because the processes may be better defined. Even gemistocytic astrocytomas have processes. Astrocytic tumors have finer chromatin than metastases. They may have chromocenters, but nucleoli if present at all should be inconspicuous (as opposed to many metastases). Metastatic tumors form clumps and are often accompanied by at least some neuroglial tissue (which has a fine fibrillated background), and will give the impression of two populations of tissue if both are present on smears. The complex microvascular changes in a smear are spread out into arborizing structures rather than being all cropped at a single level as in a tissue section. In both preparations, tumor cells tend to cling to the vessels.
Table 3C.2

Necrosis in brain lesions

Process

Differential features of necrosis

Glioblastoma Infarct

Dead vessels, pseudopalisading, coagulative Dead vessels

Metastasis

Pseudopapillary

Infection or infarct

Liquefactive, neutrophils and/or macrophages should raise non-neoplastic “flags”

Table 3C.1

Neoplastic enhancement on scans

Process

Patterns of enhancement

Glioblastoma

Irregular “shaggy” ring enhancement

Abscess

Thinner, more uniform ring enhancement

Lymphoma

Variable

Metastasis

Variable – much more edema than primary – more likely to hemorrhage

Therapeutic effects in previously diagnosed gliomas include macrophages becoming prominent, vessels becoming hyalinized and possibly less cellular appearing, necrosis in areas of tumor (or surrounding brain) which aren’t very cellular (Fig. 3C.10), a paucity of mitoses, and occasionally increased numbers of truly bizarre astrocytic nuclei with intranuclear cytoplasmic pseudoinclusions.
Fig. 3C.10

Histology – large areas of necrosis and a low level of cellularity after radiation therapy

Differential diagnosis can also include acute multiple sclerosis (MS), particularly in younger females, which may show considerable necrosis. The lesions can be incredibly mitotically active in areas and show considerable reaction from surrounding vessels. But, this will be accompanied by macrophages, perivascular cuffs of lymphocytes and evenly scattered (though perhaps large and juicy) astrocytes.

Differential Diagnosis: Abscess

Abscesses also can have ring-enhancement, many mitoses, reactive blood vessels to be confused with tumor vessels, and bizarre astrocytes. But the vessels within the brain are pushed aside by an abscess and are reactive not “glomeruloid,” the reactive astrocytes have abundant cytoplasm, the level of inflammation (Fig. 3C.11) is way over and above that of a glioblastoma, and the glioblastoma has a shaggier wall of enhancement. The fibrotic wall (Fig. 3C.12) of an abscess is not seen in gliomas. Significant numbers of neutrophils are almost never seen in primary glial tumors that have had no prior surgery, despite large areas of necrosis. Neutrophils and macrophages should make you think twice about calling the lesion a primary glioma.
Fig. 3C.11

Histology – abscess – reactive vessels, inflammation

Fig. 3C.12

Histology – abscess – fibrotic wall

Differential Diagnosis: High-Grade Oligodendroglioma

A few mitoses (Fig. 3C.13) and hypercellular nodules do not make an oligodendroglioma high grade. This can be one of the most problematic areas in frozen sections. You don’t want to make a glioma with these features high grade unless you are sure it is astrocytic. All the high-grade features in a tumor which is purely oligodendroglial only make it WHO grade III. You also don’t want to see dead or dying cells (Fig. 3C.14) and automatically assume it is a glioblastoma.
Fig. 3C.13

Smear – oligodendroglioma – mitoses

Fig. 3C.14

Smear – oligodendroglioma – scattered dying cells

Differential Diagnosis: Other Primary Lesions

PXA (pleomorphic xanthoastrocytoma) is a low-grade tumor with enough pleomorphism (Fig. 3C.15) that limited samples may be in the differential of glioblastoma. The PXA is noninfiltrative on radiology and tissue sections; if the boundary with adjacent brain isn’t available in the frozen section, the MRI scans should clinch the issue. Necrosis is not present in low-grade PXA and mitoses are few despite the bizarre nature of the cells. Anaplastic PXA could remain in the differential however.
Fig. 3C.15

Histology – PXA – large pleomorphic astrocytes

Primary CNS lymphomas may enhance, and if they do, it may be solid or ring-enhancement. They tend to be periventricular and can be multifocal. The peripheral zones of the tumor usually show “perivascular cuffing” which can be mistaken for “secondary structures of Scherer” – astrocyte tumor cells around vessels, or the other complex microvascular structures typical of high-grade glioma. The central areas with sheets of back-to-back cells show nuclei generally larger than those of glioblastoma (Fig. 3C.16) with less nuclear membrane irregularities and nucleoli that are conspicuous. Single cell necrosis is typical, something not classical for glioblastoma. Smears show the coarse chromatin, prominent nucleoli, and lack of processes better than frozen sections, and diff quik stains in particular highlight the lymphoid features.
Fig. 3C.16

Histology – PCNSL – fairly round nuclei, many of them quite large, nucleoli

PML (progressive multifocal leukoencephalopathy) can have some very bizarre astrocytes (Fig. 3C.17) and necrosis is expected. It is not unusual for PML to appear to follow white matter tracts like glial tumors do. But the macrophages and even distribution of the astrocytes should have you searching for infected oligodendroglial nuclei.
Fig. 3C.17

Histology – PML – large bizarre astrocytes, macrophages, perivascular lymphocytes

Differential Diagnosis: Metastasis

Metastases have a mass effect much more significant than their size alone would predict because of the surrounding edema, which is much more than seen with a primary tumor, in effect making their total volume higher than it would be otherwise. They have a pushing border, not the T2-weighted infiltrative borders seen with primary tumors. Metastases tend to be multiple, but the smaller ones may not yet be in evidence at original presentation, while glioblastoma can have multiple sites of proliferation which mimic ­multifocality on scans. The T2 and FLAIR images distinguish metastases from glioblastoma. The metastasis will generally not show more than very little tendency to infiltrate at the edges on frozen sections and will show two cell populations (Fig. 3C.18) on smears; gliotic brain, and balls of tumor ­usually (Fig. 3C.19). Metastases have coarser chromatin than astrocytic tumors. Many metastases have prominent nucleoli (Fig. 3C.20) as compared to astrocytic tumors which may have chromocenters, but nucleoli if present at all are usually inconspicuous. The pattern of necrosis for many metastases is a pseudopapillary one (Fig. 3C.21) as opposed to the pseudopalisading on high-grade glial lesions. The necrosis in metastases often incites an acute inflammatory reaction (Fig. 3C.22) and macrophage ­infiltration, unlike primary glial tumor necrosis, which usually does not cause much inflammatory response.
Fig. 3C.18

Smear – metastasis – two cell populations

Fig. 3C.19

Smear – metastasis – balls of cells

Fig. 3C.20

Smear – metastasis – nucleoli, coarse chromatin

Fig. 3C.21

Histology – metastasis – “pseudopapillary” necrosis

Fig. 3C.22

Smear – metastasis – inflammation and tumor cells

Differential Diagnosis: Infarct

Infarcts may be mistaken on CT for tumor. At some point in time they will enhance around the central necrosis. The macrophages present at this point in time, or red neurons (Fig. 3C.23) if it is earlier (and they are present) will make this diagnosis for you. The vessels are reactive, not the complex microvascular changes seen around necrosis in high-grade glial tumors. Dead vessels will be seen within the necrosis (Fig. 3C.24).
Fig. 3C.23

Smear – red neuron

Fig. 3C.24

Histology – dead vessels

Cautions

  • GBM is glioblastoma (no longer multiforme).

  • Macrophages in any significant numbers should always make you take a step back and reconsider whether you are looking at tumor.

  • Neutrophils are also an unusual accompaniment to ­primary glial tumor.

Case 3D A 50-Year-Old Male with Seizure and Unilateral Weakness

  • M. Timothy Smith

Clinical History

  • 50-year-old man

  • Long history of tobacco use

  • Decreased mentation, unilateral weakness, and new onset seizures

  • Exam – right hemiparesis

What Is Your Diagnosis?

Figure Discussion
Scans

The “mass effect” is a combination of the actual mass (small) and the prominent edematous reaction to the mass, which combine to cause symptoms when the tumor is still relatively small. The ring enhancement outlines an undoubtedly necrotic center (Figs. 3D.13D.3).

Pathology
Metastases have as many patterns as their original tumors do. This one is papillary with a high N/C ratio, prominent nucleoli, and well-defined (epithelial) cell borders which are all demonstrated nicely on cytologic preparations. The cells also form balls of cells on the smears as adenocarcinomas so often do (no matter where they are). There are no processes. The histology shows the fibrovascular cores, mitoses, and lymphocytic infiltrate. There is no fine fibrillar background suggesting brain in the tumor sections (Figs. 3D.43D.7).
Fig. 3D.1

Axial MRI T1 precontrast – large left hemisphere anterior lesion

Fig. 3D.2

Axial MRI T1 postcontrast – small anterior left lesion brightly enhancing with a large amount of surrounding edema (which is darker than the brain parenchyma)

Fig. 3D.3

Axial MRI T2 – vasogenic edema in white matter

Fig. 3D.4

Smear (H&E stain high magnification) – papillary groups of cells with distinct cell borders and obvious nucleoli

Fig. 3D.5

Smear (DQ stain high magnification) – ball of cells, fairly monotonous appearing nuclei with nucleoli

Fig. 3D.6

Frozen section (H&E high magnification) – papillary groups of cells with irregular appearing, hyperchromatic, pleomorphic nuclei, but no obvious mitoses

Fig. 3D.7

Frozen section (H&E high magnification) – high N/C ratio, pseudostratification of nuclei, with some nuclei at the surface of the cell (hobnail), rare mitoses

Diagnosis: Metastatic Tumor

Cerebral metastases in adults are common and may be the first sign of a systemic primary. Common primary sources are lung, breast, gastrointestinal tract, kidney, prostate gland, skin (melanoma), and thyroid gland. Most metastasize to the brain proper, whereas prostatic carcinoma seldom goes to brain parenchyma, but instead goes to adjacent bone and affects brain/spinal cord after growth and compression. Metastases in the vertebral column are commonly breast ­carcinomas, prostate carcinomas, and lymphoma. Spinal cord parenchymal metastases are unusual. MRI appearances are variable, but multiple lesions are a significant clue. Proper subclassification of metastases can await permanent sections. Systemic malignancies may affect the subarachnoid space only, producing carcinomatous meningitis. These originate from lung, breast, and stomach. Metastases are often multi­focal and well circumscribed. Pathologists are asked to intraoperatively distinguish between glial and nonglial malignancies or lymphoma. Frozen sections reveal the nonglial nature of the metastatic tumor, i.e., no fine fibrillar, vacuolated background. Deposits of metastatic carcinoma in the brain usually form groups of tumor cells that are clearly separate from the adjacent reactive neuropil. Carcinoma cells do not normally infiltrate in single cell fashion in the brain as do the cells of malignant gliomas. The notable exception is melanoma, a tumor that may infiltrate in single cell fashion, possibly because it is also of neuroectodermal origin. Papillary, ­glandular, or other patterns may be present ­recapitulating the pathology of the primary. Necrosis can be extensive (Table 3D.1).
Table 3D.1

Necrosis in brain lesions

Process

Differential features of necrosis

Glioblastoma

Dead vessels, pseudopalisading, coagulative

Infarct

Dead vessels

Metastasis

Pseudopapillary, sometimes single cell death prominent

Infection or infarct

Liquefactive, neutrophils, and/or macrophages should raise non-neoplastic “flags”

Cytological features on smears are expectedly variable depending on the primary source and resemble the FNA appearance of the primary. Epithelial cells maintain some cohesiveness, and may make balls of cells but also disperse in small groups and single cells at the edges of the larger groups. Some tumors cling to the sides of tumor vessels, without the cytoplasmic processes of primary glial tumors. A background malignant necrotic diathesis is usually present and multiple kinds of inflammatory cells are a common response. Cytoplasm quantity is expectedly variable and cytoplasmic borders are more distinct than with glial cells. Glial-like processes seldom extend from tumor cells. Tumor nuclei are large, often with central nucleoli (unusual for glial cells), and chromatin is coarser than in glial cells. Mitoses are easily found. A fine glial fibrillary background is lacking within metastases. Separate clumps of reactive glial tissue may be present, giving the impression of two separate cell populations.

Specific features of some tumors may be found. For example, the nuclear molding of small cell carcinoma, or the clear cells and vascular pattern of renal cell carcinoma may be present. Melanin may be seen in the discohesive cells of metastatic melanoma. Gland formation or cytoplasmic keratin can often be identified in metastases. Small cell lung carcinoma metastases will morphologically mimic primitive neuroectodermal tumors (PNETs). A small cell PNET-like tumor in the cerebrum of an adult is most likely a metastasis but a small cell PNET-like tumor in the cerebellum of a child is usually a medulloblastoma. A small blue cell tumor in the hemispheres can be metastatic small cell carcinoma or a cerebral neuroblastoma. A deferred diagnosis intraoperatively is appropriate; immunohistochemistry and correlation with the clinical information will be critical to the final diagnosis. Rhabdomyosarcoma occurs rarely as a primary tumor in the brain as well as the meninges. Ewing’s sarcoma and neuroblastoma may metastasize to the skull.

Differential Diagnosis: Lymphoma

Lymphomas of the brain can be either secondary or primary making about 1% of brain tumors. Primary CNS lymphomas were once rare, but now are much more common, being associated with the AIDS epidemic, transplant patients, chemotherapy patients, and other situations of immunocompromise (including age) so history is important. In order of frequency, the cerebrum, cerebellum, and epidural space are involved, often with multiple lesions. Of hematopoietic tumors, plasma cell dyscrasias predominate in skull and vertebrae. MRI often shows periventricular involvement with primary lymphomas but subarachnoid involvement with systemic lymphomas. T1-weighted MRIs are usually hypointense. Lymphoma may be multifocal and enter the differential diagnosis of meta­stases. Squash cytology displays sheets of lymphoid cells transected by mildly hyperplastic vessels. The individual cells are those of the lymphoid series showing follicular ­center cell or cleaved morphology. Most are B cell lymphomas. Plasmacytoid features may be present. Lymphomas possess cytology distinct from metastases, small cell carcinoma, and glial tumors that is best appreciated on cytologic preparations. Touch preparations from lymphomas (Fig. 3D.8) will show single cells and may show smudged nuclei characteristic of lymphoma/leukemia. Frozen sections have the typical architectural pattern of perivascular lymphoid cuffing, especially toward the edges of the tumor. The lymphoid infiltrates permeate the vessel walls, forming tumor aggregates that may show necrosis. Recognizing intraoperatively that the tumor is a lymphoma allows for flow cytometry and appropriately stops the surgery at biopsy, rather than resection.
Fig. 3D.8

Touch preparation – PCNSBL – single large cells with large nuclei, smudged nuclei in the background

Differential Diagnosis: High-Grade Glioma

High-grade glioma is infiltrative on scans and on tissue sections, in contrast to metastases. When the complex microvascular changes are glomeruloid, the diagnosis favors glioma. When there is “pseudopalisading” around the necrosis (Fig. 3D.9), rather than “pseudopapillary” structures formed by the necrosis, glioma is more likely. Astrocytic tumors have finer chromatin (Fig. 3D.10) than metastases. They may have chromocenters, but nucleoli if present at all should be inconspicuous (as opposed to many metastases). Glioblastomas can appear multifocal by imaging and can rarely have epithelial metaplasia. Their predominant morphology will display a glial fibrillary background identifying the nature of the tumor. Recognition of the glial background and infiltrative nature intraoperatively allows you to appropriately classify these tumors as primary malignancies.
Fig. 3D.9

Histology – glioblastoma – pseudopalisading necrosis

Fig. 3D.10

Smear – high-grade glioma – fine chromatin, mitoses, reactive astrocytes

Differential Diagnosis: Malignant Dural Tumors

Malignant meningioma (Fig. 3D.11) can assume spindled, very epithelioid, or clear cell morphologies causing some difficulty in distinguishing it from a dural carcinoma metastasis. Secretory meningiomas can also resemble adenocarcinomas but usually lack the usual pleomorphism, necrosis, mitotic rate, and nucleoli of a metastasis. The herringbone pattern of fibrosarcoma is frequent in meningiomas as they become more malignant. An extra frozen section from a different area may reveal a more typical meningioma pattern or psammoma bodies, thus revealing the tumor’s true nature.
Fig. 3D.11

Histology – malignant meningioma – cellular pleomorphic tumor with necrosis and mitoses

Differential Diagnosis: Primary Bone Tumors Versus Base of Skull Mets

Chordomas are slowly growing extradural tumors of bone that arise from remnants of notochord at extreme ends of the neuraxis, usually the clivus or the sacrum. Rarely do they originate along the pharynx or thoracic vertebrae. Chondrosarcoma and chordoma occur in similar locations and have passing similarities on histology also. The cytology of chordoma smear preparations shows epithelioid cells singly, and in small groups, and rows and chains of cells floating in pools of basophilic mucoid material. Bubbly or vacuolated cytoplasm (physaliphorous) may be poorly represented in smears. Nuclei are bland and mitoses are rare. The tumor usually has a lobular pattern created by fibrous septae partitioning the extracellular mucoid material (Fig. 3D.12). The extracellular mucoid material varies greatly in quantity, so some chordomas may be mostly solid. The vacuolated cytoplasm can resemble that of adenocarcinomas, but the pleomorphism, atypia, and malignant diathesis of adenocarcinoma are lacking.
Fig. 3D.12

Histology – chordoma – two cell types (one eosinophilic, the other vacuolated) in a myxoid matrix within bone

Cautions

  • History can sometimes help you recognize the tumor pattern you are seeing (despite the frozen artifacts).

  • Multiple lesions on scans are most often metastatic.

  • Melanomas can be somewhat infiltrative.

Case 3EA 70-Year-Old Male with Dense Hemiparesis and History of Kidney Transplant

  • M. Timothy Smith

Clinical History

  • 70-year-old man

  • Progressive development of a dense hemiparesis over a period of 4 days

  • Kidney transplant 3 years ago

  • Exam – unoriented ×3, receptive aphasia

What Is Your Diagnosis?

Figure Discussion
Scans

The surgery was performed because the enhancement was felt to be leptomeningeal (suggesting possible tumor or infection) rather than gyral (indicating ischemia). The diffusion scan, however, supports the impression of ischemic change (Figs. 3E.13E.3).

Pathology
Obviously all cells in the CNS with red cytoplasm are not gemistocytic. These cells have a distinctly pyramidal morphology. The change seen in the vessels is reactive with endothelial hyperplasia (Figs. 3E.43E.8).
Fig. 3E.1

Coronal MRI T1 postcontrast – left temporal lobe enhancement in a “gyral” pattern

Fig. 3E.2

Sagittal MRI T1 postcontrast – enhancement in a “gyral” pattern

Fig. 3E.3

Axial MRI diffusion – demonstrating no fluid movement (bright) in these gyral areas

Fig. 3E.4

Smear (H&E low magnification) – minor clumping of tissue with scattered cells bearing red cytoplasm

Fig. 3E.5

Smear (H&E high magnification) – a closer view of those same cells

Fig. 3E.6

Frozen section (H&E low magnification) – those same cells scattered in the tissue section

Fig. 3E.7

Frozen section (H&E high magnification) – a closer view of those same cells with the red cytoplasm

Fig. 3E.8

Frozen section (H&E low magnification) – prominent vessels with large endothelial cells

Diagnosis: Infarct

Occasionally, as in this instance, red neurons will be the diagnostic feature in an infarct. They can be mistaken for astrocytes. In contrast to the pyramidal shape of the eosinophilic neurons, gemistocytic astrocytes (Fig. 3E.9) are more globular, and multiple processes may be more or less apparent. More often, the patient is in the subacute stage of an infarct when someone clinically begins to suspect that it may be something other than “stroke.” The pathology at this time usually enters into the “necrosis of various causes” set of differential diagnoses (Table 3E.1). One of the most useful cells to look for and lead to a non-neoplastic diagnosis in the case of subacute infarct will be the macrophage (Fig. 3E.10). On frozen sections, macrophage cell borders become indistinct, and their cytoplasm fairly clear like ice crystal artifact or oligodendroglial cells with nuclei small and round like oligodendroglial cells. These cells may be difficult to recognize on frozen sections unless they are stained well (Fig. 3E.11), making cytologic preparations invaluable. On cytology, ­macrophages show a low N/C ratio, foamy/granular ­cytoplasm, debris/hemosiderin in cytoplasm (Fig. 3E.12), and small round monomorphic nuclei with chromatin pattern less dense than oligodendroglial nuclei.
Fig. 3E.9

Histology – glioma – some of the astrocytes have obvious globular eosinophilic cytoplasm (gemistocytes)

Fig. 3E.10

Smear – subacute infarct – macrophages and an astrocyte

Fig. 3E.11

Histology – subacute infarct – macrophages stuffed with debris

Fig. 3E.12

Smear – subacute infarct – macrophages with occasional hemosiderin

Table 3E.1

Necrosis in brain lesions

Process

Differential features of necrosis

Glioblastoma

Dead vessels, pseudopalisading, coagulative

Infarct

Dead vessels

Metastasis

Pseudopapillary, sometimes single cell death prominent

Infection or infarct

Liquefactive, neutrophils, and/or macrophages should raise non-neoplastic “flags”

Differential Diagnosis: Glioblastoma

In an older adult, high-grade glial tumors are often the major differential for infarct. Often the scenario will be a patient thought originally to have an infarct, but as time goes on, and repeat scans show atypical patterns of enhancement, the neurosurgeons become involved. Both infarcts and tumors may be necrotic, with gemistocytic cells that can be difficult to reliably pigeonhole as reactive or neoplastic. The higher grade the glial tumor is the more likely it is to have a lymphocytic reaction, which would also be common adjacent to infarct. Reactive blood vessels may be mistaken on frozen sections for the complex microvascular changes of higher grade gliomas. But “pseudopalisading” (Fig. 3E.13) around necrosis makes it diagnostic of tumor (true pseudopalisades are not made up of inflammatory cells, so be careful). Well developed “glomeruloid” vascular changes are also consistent with high-grade glioma. Large, hyperchromatic, irregular, “bare” nuclei are neoplastic. They are not going to be reactive astrocytes (which have a cytoplasmic reaction in addition to nuclear changes). Fortunately, most high-grade gliomas reach a level of cellularity that puts anything ­reactive out of the differential, but we all know that the attempts of the neurosurgeon to stay out of the necrotic center, often put them too far out toward the edges of the tumor. And it is always possible for what you are looking at to be infarct when the neurosurgeon is adamant that he has a tumor in front of him, because occasionally you will see infarct next to tumor.
Fig. 3E.13

Histology – GBM – piling up of nuclei around the edges of an area of necrosis

Differential Diagnosis: PML

The patient usually has a history of immunocompromise in progressive multifocal leukoencephalopathy (PML). Macrophages and perivascular lymphocytic cuffs are common to both PML (Fig. 3E.14) and subacute infarcts. The distribution on scans is usually different enough on larger wedgeshaped infarcts to make biopsy unusual, but infarcts in other white matter areas may be biopsied to differentiate them from tumor, MS, or PML. PML has bizarre astrocytes and oligodendroglial nuclear inclusions, unlike infarcts.
Fig. 3E.14

Histology – PML – bizarre astrocytes and numerous macrophages, with perivascular lymphocytes

Differential Diagnosis: MS

Macrophages and perivascular lymphocytic cuffs are common to both multiple sclerosis (MS) (Fig. 3E.15) and subacute infarcts. The common age ranges for each rarely overlap. The usual distributions on scans are different. But every year we get one or more biopsies where the patient is outside the usual age range for MS and not immunocompromised, the locations are unusual for infarcts, and the neuroradiologist can’t really tell what the process is on scans (other than probably not neoplastic). These often end up being an atypical demyelinating process, possibly tumefactive MS.
Fig. 3E.15

Histology – MS – perivascular lymphocytes, macrophages, reactive astrocytes

Differential Diagnosis: Abscess

Both infarcts and abscesses can have gliosis, macrophages, and reactive vessels. Infarcts have dead vessels within them, while abscesses tend to “push” the normal tissue away. Abscesses usually have more mitoses than infarcts. Neutrophils are not as common in infarcts as in abscesses (Fig. 3E.16). Infarcts have less tendency to incite a fibrotic reaction/wall than abscesses do (Fig. 3E.17). The wall of an abscess will be apparent on scans as a ring of enhancement.
Fig. 3E.16

Histology – abscess – reactive vessels and inflammatory cells

Fig. 3E.17

Histology – abscess – three zones from outside in – gliotic brain, fibrotic wall, necrotic center

Cautions

  • Red neurons are often pyramidal in shape (as opposed to gemistocytes).

  • Macrophages in any significant quantities should make you think twice before calling a lesion a primary tumor.

  • Don’t forget infarct may be seen next to tumor, so if the surgeon insists that there is a tumor, then suggest he may be adjacent to it.

Case 3FA 74-Year-Old Female with Headache, Confusion and Personality Change

  • Cynthia T. Welsh

Clinical History

  • 74-year-old female

  • 2-week history of confusion, headaches, personality change

  • Normal neurologic exam

What Is Your Diagnosis?

Figure Discussion
Scans

“Ring-enhancing” necrosis has a large differential which changes based on age group and immune system status. Position of the lesion as white matter centered (probably glioma) versus adjacent to ventricle (more likely PCNSL), single versus multiple lesions (could be metastatic), and the so-called open ring of MS enhancement all influence the differential. This lesion is near the ventricle and obstructing flow, causing hydrocephalus (likely a cause of the patient’s symptoms). It enhances and after fluid attenuation on the FLAIR sequence shows infiltration, not just edema surrounding the main tumor mass (unlike a metastasis) (Figs. 3F.13F.2).

Pathology
The perivascular pattern of these cells is “cuffing” the vessels, in distinction from the nonspecific look of a glial cell “secondary structure” gravitation toward vessels, or the other patterned “pseudorosette” morphology of ependymal tumors. On the frozen section it can be difficult to tell what cell type is making up the tumor, but on the cytologic preparation the lymphoid nature of these cells is obvious, making the touch preparation invaluable. On the smears, there are large cells with little cytoplasm, large mostly round nuclei, and prominent nucleoli. The chromatin is evenly clumped (Figs. 3F.33F.6).
Fig. 3F.1

Axial MRI T1 postcontrast – left periventricular fairly solid contrast enhancement

Fig. 3F.2

Axial MRI T2 FLAIR – left periventricular area dark on T2 with surrounding brighter areas demonstrating mass effect (pushing on ventricle)

Fig. 3F.3

Touch preparation (DQ stain high magnification) – very cellular with a broad range in cell size, but predominately round nuclei in all cell sizes; nucleoli are seen in the larger nuclei

Fig. 3F.4

Touch preparation (DQ stain high magnification) – closer view of cells

Fig. 3F.5

Frozen section (H&E stain high magnification) – astrocytes with obvious cytoplasm are sprinkled in a background of infiltrative pleomorphic cells

Fig. 3F.6

Frozen section (H&E stain low magnification) – elsewhere in the lesion, the infiltrating cells tend to coalesce cuff around vessels

Diagnosis: Primary CNS B-Cell Lymphoma

The common age range for PCNSL, metastases, and high-grade glial lesions tends to be similar (older adult). Immunocompromise favors PCNSL, as does a location closer to ventricles, so clinical information is important. Single cell death is common in lymphomas unlike glial tumors. Perivascular cuffs of cells predominate around the periphery of the tumor, while the center consists of sheets of cells. These may have distinct cell membranes, mimicking a sheet of epithelial cells. On cytologic preparations, the single cell character will be easily seen. Almost all primary brain lymphomas are large B-cell lymphomas. They usually have large nuclei, prominent nucleoli, and little cytoplasm just like their systemic counterparts. Recognizing the lymphoid nature of the process allows you to send material to flow cytometry, and allows the neurosurgeon to stop the procedure before resection (PCNSL is not a surgical disease).

Differential Diagnosis: Metastases (Particularly Melanoma)

One metastatic lesion in particular (melanoma) has a marked tendency to single cell infiltration, which may make it more difficult to separate out from primary tumors, both glial and lymphoid, on frozen sections. You are also likely to have single cells on the cytologic preparations for both melanoma (Fig. 3F.7) and lymphoma. The nuclear characteristics will vary depending on melanoma type, ranging from spindled to large cells with large eccentric nuclei and large nucleoli (they are generally more prominent even than the ones in PCNSBL).
Fig. 3F.7

Smear – melanoma – large single cells with large mostly round nuclei and nucleoli

Differential Diagnosis: Glioma

Frozen sections can distort lymphoma nuclei infiltrating through brain and make it difficult to tell them from glial cells. Both lymphomas and gliomas may show necrosis. It may be hard in frozen sections to tell that the cells surrounding vessels (Fig. 3F.8) are glial rather than lymphoid. Smears of oligodendroglial tumors (Fig. 3F.9) can mimic lymphoma; neither have processes, both can have single cells. The nuclei in oligodendrogliomas do not generally approach the large size of the PCNSBL nuclei though. The chromatin pattern is not clumped in oligodendroglioma cells as it is in lymphoma. Necrosis in glial tumors may be pseudopalisading (unlike lymphomas) and seldom shows the single cell apoptotic pattern that is usually prominent in lymphomas.
Fig. 3F.8

Histology – glioma – secondary structure of tumor cells around vessel

Fig. 3F.9

Smear – oligodendroglioma – small monotonous cells with a small amount of cytoplasm

Differential Diagnosis: Non-neoplastic Lymphoid Proliferations

Lymphoid infiltrates are common in many processes in brain, both neoplastic and non-neoplastic, and often form perivascular cuffs (Fig. 3F.10). Plasma cells can be an indication that the process is reactive, as can the size of the lymphoid cells which remain smaller than tumor cells.
Fig. 3F.10

Histology – toxoplasmosis – no organisms are seen in this field. The vessel on the right is surrounded by lymphocytes and plasma cells

Cautions

  • Primary lymphomas are infiltrative like gliomas.

  • Melanomas can be somewhat infiltrative.

  • Cytologic preparations (and perhaps Diff Quik stains) may make it much easier to recognize the infiltrative cell type.

Case 3GA 65-Year-Old Male with Dizziness and Left Arm/Leg Weakness

  • Cynthia T. Welsh

Clinical History

  • 65-year-old male

  • Found down, “dizzy”

  • Had been having left arm and leg weakness for 2 weeks

  • Arteriovenous malformation in 1995; craniotomy ×2

  • History: hypertension, congenital heart failure, atrial fibrillation

What Is Your Diagnosis?

Figure Discussion
Scans

Ring-enhancing lesions which approach the brain surface may be metastatic to leptomeninges or gray–white junction with growth in both parenchymal and extra-axial directions. On the other hand, they may be gliosarcomas (Figs. 3G.13G.3).

Pathology
The biphasic appearance to the tumor may be explained by a tumor which is glial but has focally taken on a more spindled appearance. There are large spindle cells with a somewhat bipolar morphology, coarse chromatin, and multiple chromocenters in addition to nucleoli and cells with more obviously fibrillary astrocytic processes (finer, multiple) (Figs. 3G.43G.7).
Fig. 3G.1

Axial MRI T1 postcontrast – ring-enhancing lesion in the white matter of the anterior right hemisphere

Fig. 3G.2

Axial MRI T2 – changes are seen extending all the way to the surface of the brain

Fig. 3G.3

Axial MRI T2 FLAIR – CSF is dark, there is very little change in the signal around the central enhancing focus

Fig. 3G.4

Smear (H&E stain high magnification) – large spindle cells with a somewhat bipolar morphology, coarse chromatin, and multiple chromocenters in addition to nucleoli

Fig. 3G.5

Smear (H&E stain high magnification) – large spindle cell (left) and more obvious astrocytes (right)

Fig. 3G.6

Frozen section (H&E stain low magnification) – areas of spindled nuclei such as seen on the smear, and adjacent more gemistocytic morphology

Fig. 3G.7

Frozen section (H&E stain low magnification) – spindled cells in fascicles, and cells with a rounder appearance to their morphology

Diagnosis: Gliosarcoma

Gliosarcoma is a high-grade glioma, generally glioblastoma, with the same prognosis. So you may ask, why include a separate case; why single it out? Mostly because of the confusion that it can cause for the pathologist and neurosurgeon. If you are expecting a glioblastoma and end up with ugly spindle cells instead, it shouldn’t necessarily make you radically change your thinking. Somewhere in the tumor will be seen the characteristic features of glioblastoma (Figs. 3G.8 and 3G.9), although perhaps not on the material sent intraoperatively. Knowing that the tumor is intra-axial (in brain), single, with the typical scanning characteristics of a primary tumor should correlate with ugly spindle cells to make you think of gliosarcoma. This subset of GBM tends to be more often seen in temporal lobe, but can be seen elsewhere.
Fig. 3G.8

Smear – GBM – large pleomorphic cells with fine chromatin

Fig. 3G.9

Histology – GBM – pleomorphic astrocytes and large scale necrosis

Differential Diagnosis: Primary or Metastatic Sarcoma

The major differential would include other spindle cell tumors, whether primary or metastatic in the leptomeninges, or possibly brain. Systemic sarcomas infrequently metastasize to the brain, dura, or skull. Primary high-grade tumors are most often of the malignant meningioma or hemangiopericytoma variety. Primary or metastatic dural spindle cell malignancies (Fig. 3G.10) are much less common than “sarcomatous” transformation of a glioblastoma.
Fig. 3G.10

Histology – sarcoma – fascicles of spindle cells with mitoses

Case 3HA 39-Year-Old Male with New-Onset Seizures

  • Cynthia T. Welsh

Clinical History

  • 39-year-old male

  • New onset seizures versus anxiety attacks

  • Head injury 3 years ago

  • Exam: normal

What Is Your Diagnosis?

Figure Discussion
Scans

This appears to be a cortical-based tumor with very little, if any, mass effect. There was no enhancement so postcontrast sequences are not shown (Figs. 3H.13H.2).

Pathology
Lymphocytic infiltration is not unusual in glial tumors, although not typical until higher grades (not seen here) in fibrillary (diffuse) astrocytoma. Certain low-grade tumors such as ganglioglioma have this same propensity for lymphocytic cuffing. The combination of low-grade cortical-based tumor and cuffing should lead to a search for other ganglioglioma clues such as eosinophilic granular bodies and neoplastic neurons. Two of the neurons on the smear appear to be binucleate. It is difficult to say if there are too many (we are in cortex) and they are not enormous (Figs. 3H.33H.5).
Fig. 3H.1

Coronal MRI T2 – left frontal thickening of gray matter in the anterior cerebral artery distribution with very little “mass effect”

Fig. 3H.2

Coronal MRI T2 FLAIR – left frontal thickening of gray matter in the anterior cerebral artery distribution with very little “mass effect”

Fig. 3H.3

Smear (H&E stain high magnification) – small capillaries, background glial cells, and several neurons

Fig. 3H.4

Frozen section (H&E stain low magnification) – gemistocytic astrocytes, lymphocytic infiltrate, and neurons

Fig. 3H.5

Frozen section (H&E stain low magnification) – gemistocytic astrocytes and lymphocytic “cuffing”

Diagnosis: Ganglioglioma

Realistically, the diagnosis of ganglioglioma is not one ­necessary at frozen section, but recognizing the neuronal aspects of the tumor can keep you from calling it high grade prematurely. Neurons (ganglion cells) are generally considered potentially neoplastic when they are too many, too large, or disorganized. Of course, that assumes you know the location of the biopsy and what appearance that tissue is supposed to have. Neurons that are binucleate are also suspect, although if you look at enough neuropathology specimens, you have undoubtedly run into binucleate neurons in “normal” brain. Knowing the clinical situation, which is most often a fairly young person with seizures and a peripheral lesion involving cortex, helps you to expect that ganglioglioma may be in the differential diagnosis. Microcysts, perivascular lymphocytic cuffing, and eosinophilic granular cytoplasmic bodies are all histologic or cytologic clues also. Features that might have made the glioma high grade, do not automatically do so when there is a ganglion cell component, so be careful not to miss these cells and overcall the tumor intraoperatively. Other CNS tumors which only occasionally have large ganglion cells as a component of the tumor include pleomorphic xanthoastrocytoma, neurocytoma, medulloblastoma, and desmoplastic infantile ganglioglioma.

Differential Diagnosis: Normal Cortex, Deep Gray Matter, Amygdala

You need to know what to expect as normal in order to decide whether to consider the neurons as possibly neoplastic. Familiarity with location of the biopsy and normal architecture at that location does not require relearning neuroanatomy. The normal rows and columns of the cortex (Fig. 3H.6) make it recognizable unless heavily overrun by tumor cells. Deep gray matter (Fig. 3H.7) can be a little more problematic unless you know the location of the biopsy. Amygdala is one area in particular where knowledge of ­location can be useful because it normally has many large neurons in clusters (Fig. 3H.8).
Fig. 3H.6

Histology – normal cortex with rows of small neurons (layers 2 and 4) across the top and bottom of the figure and the columns of layer 3 pyramidal neurons all pointing up toward the surface of the brain

Fig. 3H.7

Histology – normal deep gray matter with clustered white matter tracts going through demonstrating chiefly an oligodendroglial population

Fig. 3H.8

Histology – normal amygdala with many large, clustered neurons oriented in several different directions

Differential Diagnosis: Neurons Trapped in Tumor

This tumor obviously involves gray matter (cortex) on scans, so neurons on the histology shouldn’t be a surprise. Normal cortical neurons usually have one nucleus, are appropriately sized and shaped, have cells satelliting (normal and/or neoplastic) around them and show cortical organization. The biopsy may be too small to show the organization, however. And when the lesion is in an area with many large neurons which lack the regimented organization of the cortex, such as deep gray matter and amygdala, then it can be more difficult to tell. Knowing where the biopsy is from is fundamental to knowing size, cell type, and organization parameters. Gliomas (Fig. 3H.9) can have cells with abundant cytoplasm (gemistocytic astrocytes) which sometimes must be differentiated from neurons.
Fig. 3H.9

Histology – glioma – the ganglion cell in the center of the frame in this figure has slightly blue cytoplasm suggesting Nissl substance and may require immunohistochemistry to ultimately determine tumor type

Differential Diagnosis: DNET

Dysembryoplastic neuroepithelial tumor (DNET) is another tumor with ganglion cells which is typically seen in young people with seizures, and affects cortex. Multiple cortical nodules of oligodendroglial-like cells and glial processes surrounding microcysts with “floating” neurons (Fig. 3H.10) define DNET. These tumors may be completely removed.
Fig. 3H.10

Histology – DNET – microcysts containing neurons

Differential Diagnosis: SEGA

Large cells, some of which have neuronal characteristics (Fig. 3H.11) admixed with large gemistocytic appearing astrocytes are seen in subependymal giant cell astrocytoma (SEGA). Knowing the tissue is intra/periventricular in a patient with tuberous sclerosis (TS) goes a long way toward entering into the correct differential. Recognizing the neuronal flavor to some of these cells and calling this tumor a ganglioglioma would not actually be as problematic as calling it a gemistocytic astrocytoma (which has very negative connotations in respect to grade and prognosis).
Fig. 3H.11

Histology – SEGA – large cells some with eosinophilic cytoplasm, others with what appears to be peripheral Nissl substance

Cautions

  • All neurons are not neoplastic.

  • Neoplastic ganglion type cells are often an indication of low-grade tumor.

  • Ganglion cell tumors are graded differently – mitoses are not enough to make it high grade.

Case 3IA 25-Year-Old Female with Headache, Nausea, Blurry Vision

  • Cynthia T. Welsh

Clinical History

  • 25-year-old female

  • Headaches, blurry vision ×2 weeks

  • Intermittent nausea

  • Exam:
    • Slight ptosis left upper eyelid

What Is Your Diagnosis?

Figure Discussion
Scans

The septal attachment rather than an origin from the lateral wall of the ventricle or from choroid plexus narrows the differential diagnosis. Neurocytomas characteristically heterogeneously enhance. An ependymal origin would still be possible for the scan appearance (Figs. 3I.13I.2).

Pathology
The frozen section makes it difficult to tell the tumor cell type. The smears once again save the day by making it abundantly clear that these are small monotonous round nuclei. There are areas where the nuclei surround fine fibrillar material in neuronal rosettes. And the vessels are exclusively capillaries. There is no cytoplasmic clearing or microcalcifications (Figs. 3I.33I.5).
Fig. 3I.1

Axial MRI T1 precontrast – intraventricular tumor attached to septum

Fig. 3I.2

Axial MRI T1 postcontrast – some enhancement

Fig. 3I.3

Smear (H&E stain high magnification) – fine capillaries and numerous small round nuclei

Fig. 3I.4

Smear (H&E stain high magnification) – round nuclei, some condensation of chromatin at nuclear rim (rare chromocenters also), and occasional central nucleoli

Fig. 3I.5

Frozen section (H&E stain high magnification) – scattered astrocytes, and many cells with frozen distortion and hyperchromaticity of nuclei, as well as a little rim of eosinophilic cytoplasm

Diagnosis: Neurocytoma

Within a ventricle, it can be possible to make neurocytoma the top ten choices for differential diagnosis when it has the distinct location within the septum. Extra-ventricular neurocytomas are more problematic. There is considerable overlap on histology between neurocytoma and oligodendroglioma. Both have haloes, microcalcifications, and a fine capillary architecture. Both can have microcysts. Neurocytoma nuclei on smears have a salt and pepper chromatin and do not generally have cytoplasm attached, but often sit in small patches of background matrix. The neuronal rosette is the distinguishing characteristic that makes a monotonous small round cell tumor recognized as a neurocytoma. These can be seen on sections but also in smears. It is important to distinguish between the well-­circumscribed (removable) neurocytoma and the infiltrative oligodendroglioma (which is usually not possible to remove entirely and will eventually return, often at a higher grade).

Differential Diagnosis: Oligodendroglioma

Central neurocytomas were misdiagnosed as oligodendrogliomas for years until they were recognized as a separate tumor category. It is probable that extra-ventricular neurocytomas continue to be misdiagnosed. They have microcalcifications, small round nuclei, and abundant capillaries, as well as enhance (though low grade) just like oligodendrogliomas. Oligoden­drogliomas do not necessarily have haloes (Fig. 3I.6), and neurocytomas frequently do. In addition, however, neurocytomas have neuronal rosettes. They do not infiltrate cortex like oligodendrogliomas (Fig. 3I.7) are so inclined to do. Smears that have not had too much pressure applied may show small rims of cytoplasm attached to nuclei in oligodendrogliomas (Fig. 3I.8).
Fig. 3I.6

Histology – oligodendroglioma – cellular tumor with small nuclei and no haloes

Fig. 3I.7

Histology – oligodendroglioma – tumor cells infiltrating ­cortex and satelliting around vessels and neurons

Fig. 3I.8

Smear – oligodendroglioma – single cells and small groups of small nuclei which are round to oval and have small rims of cytoplasm attached

Differential Diagnosis: Ependymoma

The differential prior to actually looking at the pathology may include ependymoma (intraventricular location!), but seldom does after microscopy of the tissue. Ependymal nuclei are more oval on cytology (Fig. 3I.9), ependymal rosettes may be seen on either cytologic preparations or on frozen section (Fig. 3I.10), and perivascular pseudorosettes are usually common. Clear cell ependymoma may resemble neurocytoma more than other subtypes because of the clear cells, microcalcifications, and sparseness of perivascular rosettes.
Fig. 3I.9

Smear – ependymoma – an ependymal rosette

Fig. 3I.10

Histology – ependymoma – even on frozen section the relatively anuclear areas around the vessels are usually apparent if you look closely

Differential Diagnosis: Metastatic Small Cell Carcinoma

Interestingly enough, despite the heavy vascularity of choroid plexus and the lack of blood–brain barrier there, metastases seldom appear inside ventricles preferentially. The nuclear molding, necrosis (including single cell apoptosis), and irregularity of the nuclei in a metastatic small cell carcinoma (Fig. 3I.11) would be distinct from neurocytoma especially if cytopreparations are available.
Fig. 3I.11

Histology – small cell carcinoma – necrosis, mitoses, and relatively small cells with salt and pepper chromatin and no nucleoli

Differential Diagnosis: Subependymoma

The pattern of relatively anuclear areas in subependymoma is different than the neuronal rosette pattern of neurocytoma. Instead, in subependymoma you see round to oval nuclei in clusters with cleared areas between clusters (Fig. 3I.12). The level of cellularity varies considerably, but is less than that seen in the center of neurocytomas.
Fig. 3I.12

Histology – subependymoma – sparsely cellular tissue with clusters of nuclei embedded in the neuropil alternate with relatively anuclear areas. The vessels are somewhat hyalinized

Cautions

  • All tumors with haloes are not oligodendrogliomas.

  • An intraventricular tumor that looks like an oligodendroglioma probably is not one.

Case 3JA 21-Month-Old Male with Developmental Regression

  • Cynthia T. Welsh

Clinical History

  • 21-month-old male

  • Decline in gross motor skills

  • Exam
    • Increased muscle tone

    • Brisk reflexes

    • Ataxic even while sitting

What Is Your Diagnosis?

Figure Discussion
Scans

The scans show an intraventricular lesion which does not enhance very brightly, in a child. It is iso-intense on both T1 and T2 sequences (Figs. 3J.13J.3).

Pathology
The tissue does not squash or smear well, but the papillary nature can be seen. The individual nuclei are oval and mono­tonous with a suggestion of eccentricity; perhaps a columnar cell pattern. The frozen sections bear this out, with a columnar covering to the papillae which is still somewhat “cobblestone” in appearance in areas, but more pseudostratified in others. This tissue fragment is not more voluminous than normal choroid plexus, but is more cellular (Figs. 3J.43J.8).
Fig. 3J.1

Axial MRI T1 precontrast – left posterior lateral ventricle mass iso-intense to brain

Fig. 3J.2

Axial MRI T1 postcontrast – choroid plexus vessels brighter than the mass, which does enhance

Fig. 3J.3

Axial MRI T2 – bright CSF highlights the mass which is again iso-intense to brain

Fig. 3J.4

Smear (DQ stain, low magnification) – papillary architecture

Fig. 3J.5

Smear (DQ stain, higher magnification) – one papillary group, and individual cells

Fig. 3J.6

Smear (DQ stain, high magnification) – oval, eccentric, monotonous nuclei

Fig. 3J.7

Frozen section (H&E stain low magnification) – papillary groups with congested vasculature

Fig. 3J.8

Frozen section (H&E stain high magnification) – round to oval nuclei with coarse chromatin, columnar cytoplasm

Diagnosis: Choroid Plexus Papilloma

Intraventricular tumors in the pediatric age group are most often ependymomas, with choroid plexus tumors being second in frequency. Ependymomas may occasionally be papillary. The most common grossly frond-like tissue from ventricle is actually choroid plexus (normal or reactive) that the neurosurgeon has encountered on the way to the tumor. Volume of tissue can often be a first indication that what you are dealing with is not normal choroid plexus so it is helpful to be familiar with how much is normal. On frozen section, the papilloma will have more cellular crowding, with loss of the normal “cobblestone” look of normal choroid plexus (Fig. 3J.9). The tissue doesn’t smear well, but some individual columnar appearing cells will be seen. The papilloma has papillary structure, but higher grade lesions often become focally more solid, cellular, and pleomorphic. Atypical ­papillomas have increased mitotic activity.
Fig. 3J.9

Histology – normal choroid plexus with a fibrovascular core and single cell layer covering the core

Differential Diagnosis: Papillary Ependymoma

Intraventricular tumors in the pediatric age group are most often conventional ependymomas, with choroid plexus tumors being second in frequency. Intracranial ependymomas may occasionally be papillary (Fig. 3J.10), and so may enter the differential diagnosis. Instead of the fibrovascular core of choroid plexus tumors, ependymomas have a delicate neuropil core. Despite the name, myxopapillary ependymomas are often NOT papillary in appearance and the perivascular pseudorosettes denote the ependymal nature of the tumors. They seldom occur in the cranium. Choroid plexus papillomas are benign tumors, although they may spread through the CSF; ependymomas require CSF analysis and scans to evaluate for drop metastases. They also require additional treatment that the papilloma does not need.
Fig. 3J.10

Histology – ependymoma – the area between the nuclei and the vessel consists of the fine processes of ependymal cells

Differential Diagnosis: ELST

Knowing that the location is somewhere in temporal bone, should make an endolymphatic sac tumor (Fig. 3J.11) (ELST) enter the differential diagnosis. These tumors are papillary and can have calcifications like choroid plexus tumors, although psammoma bodies are unusual. ELST most often have only a single layer of surface cells. ELST can also have intranuclear pseudoinclusions like papillary cancer of thyroid, as well as colloid-like material. Extension of the ELST often results in cerebellar and further skullbase involvement. The diagnosis should trigger exclusion of von Hippel–Lindau syndrome clinically.
Fig. 3J.11

Histology – ELST – papillary structures with fibrovascular cores and bland cells covering the cores

Differential Diagnosis: Papillary Craniopharyngioma

Papillary craniopharyngioma (Fig. 3J.12), in contrast to the more common adamantinomatous subtype, has a tendency to involve the third ventricle. It may then enter into the differential of papillary intraventricular tumors. The distinctive basal ­palisading of cells and intracellular bridging may usually be easily distinguished on frozen section. These have less tendency toward stellate reticulum and do not have the “wet keratin” and calcification pattern of the adamantinomatous subtype.
Fig. 3J.12

Histology – craniopharyngioma – papillary structure covered by squamous epithelium with loose stellate reticulum centrally and focal keratinization

Differential Diagnosis: Papillary Metastatic Tumor

Most papillary tumors metastatic to the CNS are adenocarcinomas (Fig. 3J.13). Fortunately, few are low grade enough to seriously enter the differential with choroid plexus papilloma. They may be considered in the differential with higher grade choroid plexus neoplasms, although the choroid plexus carcinoma is seldom seen outside of childhood.
Fig. 3J.13

Histology – metastatic adenocarcinoma – papillary tumor which is mitotically active and demonstrates nucleoli

Differential Diagnosis: Papillary Meningioma

Meningiomas can occur in ventricles and they are rarely papillary, although many tend to fall apart and have a papillary type look in some areas (Fig. 3J.14). Both tumors can have psammoma bodies. The characteristic whirls and/or intranuclear pseudoinclusions will often be present somewhere within the tissue of a meningioma.
Fig. 3J.14

Histology – meningioma – intranuclear pseudoinclusions (arrow) help to discriminate from some of the other tumors

Cautions

Normal choroid plexus is the most common papillary tissue to be found in the ventricles.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineMedical University of South CarolinaCharlestonUSA
  2. 2.Department of Pathology and Laboratory MedicineMedical University of South CarolinaCharlestonUSA

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