97 M.A. Hayat (ed.), Tumors of the Central Nervous System, Volume 6: Spinal Tumors (Part 1),
Tumors of the Central Nervous System 6, DOI 10.1007/978-94-007-2866-0_13,
© Springer Science+Business Media B.V. 2012
13
Abstract
Introduction
Gangliogliomas are (mostly) low grade neuroepi- thelial neoplasms characterized by cellular popu- lations comprising both glial cells, usually astrocytes, and large neurons (“ganglion cells”).
The clinical, neuroimaging, and neuropathologi- cal aspects of gangliogliomas of the brain are reviewed in a companion chapter in this volume (Miller and Paullus 2010 ) . In this chapter, I will discuss the special aspects of spinal cord gangliogliomas.
As with gangliogliomas of the brain, these are mostly tumors of children and young adults, although examples are occasionally encountered in older patients. Cord gangliogliomas, as low grade tumors, tend to grow only slowly. Since by virtue of their location they cannot present with seizures, as their cerebral counterparts often do, they usually manifest rather late in their clinical course as judged by their size when compared to the size of the cord as an environment, in contrast to most gangliogliomas of the brain. This has implications for their appearance in MRI studies, as will be discussed below.
As with other neuroepithelial tumors of the spinal cord, gangliogliomas are intrinsic intramedullary neoplasms. This greatly compli- cates their pathological diagnosis, as in many if not most healthcare environments standard prac- tice for many years has been to do minimal diag- nostic biopsies of intramedullary spinal cord tumors and then follow with radiation therapy or other adjunctive therapy as indicated by the diag- nosis. Radical excisions of cord tumors has mostly been reserved for ependymomas, which are virtually unique in their sharp circumscrip- tion from adjacent spinal cord parenchyma, allowing their excision (often en bloc ) rather than just biopsy. In the last three decades, this has partly changed, as a pioneering practice of radi- cal excision for intramedullary spinal cord tumors of the late Fred Epstein MD at NYU Medical Center (Epstein and Epstein 1982 ; Epstein 1986 ; Epstein et al. 1992 ; Shrivastava et al . 2005 ) and later at the Beth Israel (NY) Institute of Neurology and Neurosurgery came to be accepted by more
and more pediatric neurosurgeons (many Epstein trainees themselves) (McGirt et al . 2007 ) . The difference between attempting neuropathological diagnosis of an intramedullary cord tumor from a few shreds of tissue from the edge of the mass as compared to tissue from a gross total excision should be obvious, and indeed when we com- pared diagnoses of previously biopsied patients who later came to Epstein for defi nitive surgery there was a substantial difference in diagnosis based largely on the greater volume of tissue made available for neuropathological examina- tion (Miller et al. 1993 ) .
What may be termed the “conventional view” of spinal cord gangliogliomas, then, has been that these are very rare neoplasms, consti- tuting about 1% of all intramedullary spinal cord tumors (Park et al . 1993 ) . While several articles or chapters have been cited for this number, all of them directly or indirectly cite data from a chapter by Zimmerman ( 1971 ) . It should be noted that Zimmerman reported 7 gangliogliomas from a total of 602 spinal cord
“tumors”, but these included metastatic neo- plasms, extramedullary tumors such as menin- giomas, and even infl ammatory conditions. In fact Zimmerman lists only 67 gliomas of all types, so that the 7 gangliogliomas constituted 11% of intramedullary glial tumors in the series he was describing. In contrast, with the aid of much larger tissue samples, combined with immunohistochemical stains as further adjuncts to diagnosis, the NYU case series of all intramedullary spinal cord tumors in children had over 26% gangliogliomas (Constantini et al . 1996, 2000 ; Miller 2000 ) . Using the same large amounts of tissue from similar surgical procedures, and the same immunohistochemi- cal stains, I found that adult intramedullary spinal cord tumors included only 10% ganglio- gliomas (Miller 2000 ) , so the higher number in the pediatric population was not likely to be the result of over-diagnosing gangliogliomas because, for example, of a misinterpretation of the immunohistochemical data. Equally, there is no published justifi cation for lower estimates of the proportion of intramedullary spinal cord tumors which are gangliogliomas.
Clinical Presentation, Imaging
Gangliogliomas of the spinal cord, like other intramedullary neoplasms, present either with motor defi cits, pain, or spinal deformity. In chil- dren, especially very young children, a head chronically tilted to one side, motor developmen- tal delay, abnormal gait (toe walking, eg ), and scoliosis are all more common than pain. In adults the cases are probably too few to make generalizations, but pain is not usually a promi- nent early symptom of intramedullary ganglio- gliomas, in contrast to patients with ependymoma who much more frequently present with pain. In unusual cases, patients with intramedullary spi- nal cord neoplasms present with signs and symp- toms of hydrocephalus, which goes unexplained until the spinal cord neoplasm is discovered (for review see Miller 2009 p. 305).
When the large NYU experience with spinal cord gangliogliomas was reviewed, and compared with data from intramedullary tumors of other histologic types, we found that gangliogliomas were typically longer, that is they involved more of the spinal cord length, than other glial tumor types (Patel et al . 1998 ) . The mean length in ver- tebral body segments for gangliogliomas was eight, whereas for cord astrocytomas and ependymomas the mean lengths were each four vertebral segments. Notably, quite a few of the gangliogliomas were “holocord” tumors, that is the entire length of the spinal cord was involved by the tumor. These observations may be com- pared with those of case reports: Lotfi nia and Vahedi ( 2009 ) described a tumor involving C2–C7; Satyarthee et al. ( 2004 ) described two cases, one extending from the cervicomedullary junction to T2, the other a holocord tumor; Park et al . ( 2000 ) described fi ve cases, with tumors from the medulla to T3, from C5 to T1, from T2 to T3, from T8 to T9, and the last a holocord tumor; Hamburger et al. ( 1997 ) described two cases with tumors from C2 to T2 and from T12 to L2; and Cheung et al . ( 1991 ) reported two cases each involving most of the length of the cord.
From these and other descriptions, ganglio- gliomas are not otherwise distinctive in MRI scans.
Intramedullary spinal cord tumors usually expand the spinal cord throughout all or most of the involved segments. The tumors are usually bright in T2-weighted images, but have variable signal intensity in T1-weighed images, being most often described as hypointense compared to the spinal cord, but not infrequently being seen as isoin- tense or even focally hyperintense. They usually enhance with the administration of gadolinium, as do other low grade spinal cord neoplasms; the enhancement may be inhomogeneous. They may contain cysts or be bordered by cysts; we (Patel et al . 1998 ) found that cysts were more common in spinal cord gangliogliomas than in cord astro- cytomas or ependymomas. The tumors usually grew eccentrically in the cord as seen in axial (cross) sections, in contrast to ependymomas which were usually central and symmetric, but not unlike cord astrocytomas. More ganglio- gliomas were in cervical levels than other cord levels.
Pathology
The same issues that complicate the diagnosis of gangliogliomas in the brain (Miller 2009 ; Miller et al. 1993 ; Miller and Paullus 2010 ) can arise in the spinal cord. The tumor neurons are not homo- geneously distributed in the neoplasms, in fact they are often clumped, so that some samples may contain few or none, leading (when these are the only samples in something other than a radi- cal excision) to an erroneous diagnosis of astro- cytoma (Fig. 13.1a , b). The tumor neurons may be mistaken for entrapped normal neurons in an infi ltrating astrocytoma. Large astrocytic cells in
“pure” astrocytomas may mimic neurons, lead- ing to an erroneous diagnosis of ganglioglioma.
While the presence of signifi cant desmoplasia may be suggestive of ganglioglioma, as can be a vigorous small cell lymphoplasmacytic reaction, neither of these fi ndings is suffi ciently specifi c to allow a diagnosis. Identifi cation of ganglioglioma distinct from astrocytoma requires recognition that the neurons are abnormal, either because of features seen in the H&E stains such as binucle- ation (Fig. 13.1b ) or overtly dysplastic shapes
(Fig. 13.1a , b), or with immunohistochemistry. In this regard several immunohistochemical fi nd- ings are important, especially when interpreted in the context of stains for myelin or axons which help identify the location of the tumor in white matter or gray matter.
Of primary importance is the H&E appear- ance of the tumor (it is a given that one must be examining a tumor, and not a biopsy of spinal cord with infl ammatory, demyelinating, or no disease). When we fi rst published our descrip- tions of these tumors, both clinical-pathological (Constantini et al . 1996, 2000 ) and neuroradio- logical (Patel et al . 1998 ) , we encountered sig- nifi cant controversy, which in part was due to a misunderstanding as to how we interpreted the immunostains and how important the immuno- histochemistry was to our diagnoses. It should by now be clear (there were published letters to the editors and answers, which need not be cited here) that the large majority of the spinal cord gangliogliomas in our published series were rec- ognized as such fi rst by H&E features. These diagnoses were all reviewed by myself and Dr Lucy Rorke (now Rorke-Adams) of Children’s Hospital of Philadelphia, and we agreed on all of the diagnoses before publishing any. In some of the cases, our initial reviews had different diag- noses, and so we met and examined those cases together using a microscope with two viewing heads, and so resolved any differences.
In cases where we suspected ganglioglioma but were not certain, immunostains then became important. Synaptophysin immunohistochemis- try was, and remains, of great utility. I and col- leagues (Miller et al . 1990 ) described that neoplastic ganglion cells had a granular perikaryal surface immunoreactivity not seen in any normal neurons of the cerebral cortex, basal ganglia, hip- pocampus, amygdala, thalamus, cerebellum, or brainstem. In our initial report no normal spinal cord neurons had this pattern either, but Zhang and Rosenblum ( 1996 ) showed some synapto- physin immunostains from autopsy specimens that had somewhat similar surface immunoposi- tivity. Later, Quinn ( 1998 ) claimed to show simi- lar patterns in normal brain neurons, and called into question all of our diagnoses of ganglio- glioma in brain and cord at NYU.
Subsequent examinations by us of surgically excised large cord segments (taken for pain relief in patients with complete paralysis and sensory loss due to malignant tumors below the levels of the resections) and of autopsy-obtained cord specimens showed that the surface immu- nopositivity described by Zhang and Rosenblum was on anterior horn cells (and no other spinal cord neurons), but that most of it was on den- drites and axons and not on the cell bodies, unlike the fi ndings in our cases of ganglioglioma (Fig. 13.1c , d). The differences, however, could be subtle. Of greater utility was that in the cord
Fig. 13.1 Diagnostic histopathology of spinal cord gangliogliomas. ( a ) This example of a spinal cord gan- glioglioma has numerous abnormal neurons clustered in this focus. The neurons vary in size, several have nuclei displaced to one side of the cell body, and the shapes of the cell bodies vary considerably. H&E, 40×. ( b ) Another cord ganglioglioma has only sparse neurons in some areas, since the neurons in these tumors are not evenly distributed. Here, in this paucicellular focus, one of the three large ganglion cells present is binucleate. H&E, 40×. ( c ) Normal spinal cord, longitudinal section through anterior horns, showing the distinctly circumscribed neuropil immunoreactivity for synaptophysin. 10×.
( d ) Anterior horn cells from normal spinal cord have some perikaryal surface immunopositivity, but mostly have denser granular immunoreactivity on dendrites and axons; note the neuropil background immunopositivity.
( e ) A tumor (here a fi brillary astrocytoma, not a ganglioglioma) infi ltrating in spinal cord white matter.
The myelinated fi bers are clearly seen as parallel eosino- philic linear structures. H&E, 40×. ( f ) A ganglioglioma with its sparse tumor ganglion cells infi ltrating spinal cord white matter. The background contains some myeli- nated axons, visible as blue linear structures. Luxol Fast Blue/H&E combination stain, 40×. ( g ) Synaptophysin immunoreactivity of neoplastic ganglion cells in a spinal cord ganglioglioma. Contrasted with normal anterior horn cells (Fig. 13.1d ), the tumor cells have more uni- form and intense granular surface perikaryal immunore- activity, and lack the dendritic or axonal processes with heavy immunostaining which characterizes the normal neurons. 40×. ( h ) Spinal cord ganglioglioma with immu- nopositivity for GFAP in tumor astrocytes and none in tumor neurons. 40×
gray matter, there was also a typical granular neuropil background immunopositivity, as we had previously described for all cerebral gray matter (Fig. 13.1c ). In cases of intramedullary spinal cord neoplasms, then, when there was a question as to whether large neuron-like cells were neoplastic ganglion cells or native neu- rons, it was possible to discriminate conclu- sively when the neurons with surface perikaryal synaptophysin immunopositivity were located in myelinated white matter in resection speci- mens, the white matter being identifi ed some- times just by H&E appearance (Fig. 13.1e ) but otherwise both by Luxol Fast Blue stains for myelin (Fig. 13.1f ) and silver stains or neurofi l- ament protein immunostains for parallel bundles of axons (not illustrated), neither of which appear in anterior horn gray matter. Equally, when cells suspicious for tumor ganglion cells resided in a gray matter neuropil of background synaptophysin positivity, a diagnosis of gan- glioglioma could be avoided absent better evi- dence. In contrast to the pattern of synaptophysin immunopositivity for normal anterior horn cells, ganglion cells of gangliogliomas have denser coarse granular perikaryal surface immunoposi- tivity, and they generally lack conspicuous den- drites and axons (Fig. 13.1g ).
Other immunostains can support a diagnosis of ganglioglioma. Anterior horn cells, and other cord neurons, are immunopositive for Neu-N;
thus when tumor neurons are identifi ed with syn- aptophysin or neurofi lament protein immunos- tains, but are Neu-N negative, or less consistently and intensely Neu-N immunopositive, this offers confi rmation that these neurons are abnormal, ie neoplastic (see Miller and Paullus 2010 ) . The presence of immunoreactivity for neurofi lament protein identifi es cells as neuronal, but as in the differential diagnosis of cerebral gangliogliomas this alone does not establish whether such neu- rons are entrapped normal elements or neoplastic cells. If the question is not whether neurons are native spinal cord cells entrapped in an infi ltrat- ing tumor or are neoplastic ganglion cells, but rather one of are they neuronal tumor cells or neoplastic astrocytes, then in addition to neuronal
markers a GFAP immunostain, which marks astrocytic tumor cells but not tumor neurons, can be helpful (Fig. 13.1h ).
There are high grade or “anaplastic” exam- ples of ganglioglioma. As described in the chap- ter on brain examples (Miller and Paullus 2010 ) ordinary low grade examples are classifi ed as WHO Grade I tumors but are commonly better regarded as Grade II neoplasms given proven tendencies to recur locally and, rarely, to “degen- erate” or progress in grade to aggressive high grade tumors. The aggressive examples, whether de novo or derived from prior low grade tumors, are classifi ed as WHO Grade III tumors. These have no special features in the spinal cord, except perhaps (like high grade astrocytomas here) to have a greater propensity for cerebrospinal fl uid dissemination.
Treatment and Prognosis
As with cerebral gangliogliomas the preferred clinical approach to spinal cord gangliogliomas is gross total excision wherever possible. This is usually feasible, but there are some cautions:
such surgical procedures for any intramedullary spinal cord tumor are done now only with exten- sive intraoperative neurophysiological monitor- ing, including motor evoked potentials as well as sensory evoked potentials, and loss of amplitude of such responses can serve as a warning to the neurosurgeons that they may be extending their resections into functional, and important, spinal cord parenchyma. The neurosurgical literature amply covers these technical issues which are beyond the scope of this review. Radiation ther- apy is reserved for documented anaplastic exam- ples. Local recurrence is similarly best treated with re-excision.
Most children and adults with gangliogliomas of the spinal cord have a good oncologic out- come, that is there tumors after removal do not recur and they do not die from disseminated dis- ease. Those with anaplastic gangliogliomas are clearly at higher risk for a bad oncologic out- come. Neurologic outcome after radical surgery
has been shown to depend largely on preopera- tive status, and while many patients have additional short-term defi cits immediately after radical surgery most recover to their baseline with rehabilitation.
Other Glioneuronal Tumors in the Spinal Cord
The same spectrum of neuroepithelial tumors with mixed glial and neuronal differentiation as is seen in the brain occurs in the spinal cord. This includes parenchymal neurocytomas and their variants, some with ganglion cells, and some with prominent neurocytic fi brillary rosettes (Miller et al . 1993 ; Miller 2009 ) . The histopatho- logical diagnostic problems these tumors present is the same in the cord as in the brain, and they require no further illustration here as these are discussed in the chapter in this volume on gan- gliogliomas and other glioneuronal tumors (Miller and Paullus 2010 ) .
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