Spinal Cord Tumor - Tumors of the Central Nervous System Volume 6

Oligodendroglioma: Diagnosis

Addisalem T. Makuria , Elisabeth J. Rushing ,

and Metin Ozdemirli

Introduction

Spinal cord oligodendrogliomas are rare, com- prising <2% of all spinal cord tumors and 1.5%

of oligodendroglioma overall (Fortuna et al.

1980 ) . The fi rst case of spinal cord oligodendroglioma was reported by Kernohan et al. in 1931 . Subsequently, more than 52 cases have been doc- umented both in children and adults (reviewed by Fortuna et al. 1980 ; Fountas et al. 2005 ; Guppy et al. 2009 ) . Although lesions can arise anywhere along the spinal cord, the most common site is the thoracic followed by cervical spine. Conus and fi lum terminale are other frequent sites of involve- ment. In addition, tumors can shed cells into the CSF spreading along the subarachnoid space and secondarily involving the leptomeninges or ven- tricular systems. Although oligodendrogliomas are rare in children, most leptomeningeal and spinal cord tumors occur in the fi rst decade of life with signs and symptoms of increased intracranial pressure. In children, most tumors are fatal in less than 2 years (Korein et al. 1957 ; Daum et al.

1974 ; Ng and Poon 1999 ; Rossi et al. 2009 ) . The cell of origin of oligodendroglioma has not been identifi ed; however, several investigators have postulated that these tumors originate from a pro- genitor cell (Makuria et al. 2007 ) . Histologically, tumors are composed of oligodendrocyte-like clear cells that often pose a diagnostic challenge, particularly if they are intraspinal. In some instances, neoplastic cells disseminate extensively in the leptomeninges, despite low-grade morphology.

Imaging studies, especially MRI with contrast, may show diffuse leptomenigeal enhancement with or without enlargement of the involved segment of the spine and an enhancing mass.

In the intramedullary compartment, the principal differential diagnosis includes oligodendroglioma

and extraventricular neurocytoma. Although immunohistochemical and ultrastructural investi- gations can be helpful in such cases, signifi cant overlapping features prove diffi cult to distinguish between the two entities. Rarely, clear cell ependymoma enters as a consideration;

however, ultrastructural study can usually resolve this dilemma. More recently, the application of molecular diagnostic techniques to certain types of primary central nervous system (CNS) tumors has increased the diagnostic accuracy over con- ventional microscopy. At the same time, diagnosis based on signature molecular characteristics raises important nosological questions.

Codeletion of 1p/19q detected by FISH is rare in children, particularly under the age of 10 years, and does not seem to be associated with the pro- longed survival seen in adults in anaplastic oligodendrogliomas (Pollack et al. 2003 ; Raghavan et al. 2003 ; Kreiger et al. 2005 ) .

Rarely, oligodendrogliomas arise in the leptomeninges and grow in the subarachnoid space without connection to spinal cord or brain parenchyma and are classified as primary leptomeningeal oligodendrogliomas (PLO) or primary leptomeningeal gliomatosis (PLG) (Chen et al.

1995 ; Rogers et al. 1995 ; Bourne et al. 2006 ; Ozkul et al. 2007 ; Mathews et al. 2009 ) . Since only few such cases have been reported, the diagnosis and classifi cation of this group of tumors is challenging and mandates exclusion of the more common leptomenigeal dissemination from a parenchymal tumor (Corsten et al. 2001 ; Bourne et al. 2006 ) . The criteria proposed for the diagnosis includes an extramedullary tumor that lacks attachment to the underlying parenchyma, no evidence of primary tumor in neuraxis and the existence of a capsule around tumor. These criteria have been challenged by Chen et al. ( 1995 ) , high index of suspicion is required for the timely diagnosis of these tumors.

Distinction from other spinal cord tumors is crucial due to differences in patient management and long-term prognosis.

Keywords

Spinal cord • Oligodendroglioma • Primary leptomeningeal gliomatosis

who suggested that the diagnosis can only be established after complete neuroanatomical examination to exclude tiny parenchymal foci within the brain or spinal cord. In PLO/PLG, the characteristic MRI fi nding of diffuse contrast enhancement of the leptomeninges without enlarge ment or the presence of mass within the involved spinal cord segment resembles chronic meningitis. Although the cell of origin of leptomeningeal gliomas is unknown, it has been postulated that it is derived from ectopic nests of glial tissue in the subarachnoid space. According to this theory, glial cells migrate from the CNS through microscopic defects in the pia mater during devel- opment (Chen et al. 1995 ) . Histologically, these tumors are similar to oligodendriogliomas, and in some cases, the signature molecular feature of 1p/19q deletion has been observed.

There are few reported cases of “holocord”

oligodendroglioma, i.e. tumor extending 19–20 cord segments of spinal cord in the literature.

In all cases, patients were less than 16 years old and the tumor extended from the cervical to the lumbar region. Patients were often initially referred for orthopedic evaluation because of scoliosis, which usually preceded neurologic decom pensation (O’Brien et al. 1968 ; Pagni et al.

1991 ; Ushida et al. 1998 ) .

Clinical

The most common spinal cord level for oligoden- drioglioma is thoracic (30%), followed by cervical (25%), and lumbar (5%). In the majority of patients, pain is the presenting complaint (69.3%) as observed in the review by Fortuna et al. ( 1980 ) . Other symptoms include weakness, twitching and contractures, paresthesias, and increased intracranial pressure. Less common symptoms include the sudden onset of cauda equina syndrome and meningeal symptoms. Sphincter disturbance has not been observed as an initial symptom. Children with spinal cord oligodendroglioma may present with irritability, macrocephaly and regression of the ability to walk.

On physical examination, most patients have sensorimotor defi cits or isolated motor deficits, decreased or absent reflexes, and

meningeal syndrome. Although very rare, cerebral symptoms may appear before spinal cord symptoms (Guppy et al. 2009 ) . Raised intracranial pressure appears to be a distinguishing feature of spinal cord oligodendroglioma (Fortuna et al. 1980 ; Guppy et al. 2009 ). Acute onset of intracranial hypertension, with sudden elevation and spontaneous remission, or even death has been reported in some cases of oligodendroglioma. Precipitous decompensation has been attributed to the tendency of these tumors to bleed spontaneously.

Unlike their cerebral counterparts, which are slightly more common in males, spinal oligodendrogliomas lack sex preference. In addition, the average age for spinal cord oligodendroglioma is lower than that for cerebral examples (28 years versus 40 years). Approximately 30% of spinal tumors occur in the fi rst two decades of life, com- pared to 12% of cerebral oligodendrogliomas (Fortuna et al. 1980 ) . The number of pediatric cases has increased over the past decade, which has been attributed to the increased incidence and/or detection in children and/or the underre- porting of adult cases.

The clinical presentation in patients with PLO/PLG is distinctive, and may mimic chronic meningitis. The age at presentation ranges from the fi rst to the seventh decade of life. The onset is usually insidious and is marked by non-focal symptoms such as headache and seizures. Physical fi ndings may include signs of meningeal irritation, mental status changes, incomplete cranial nerve palsies, papilloedema, weakness and urinary inconsistency. Patients may present with focal neurological defi cits or they develop them subsequently (Chen et al. 1995 ) . The cerebrospinal fl uid of patients with PLO/PLG consistently shows a disproportionately elevated protein and normal glucose level. Diagnosis based on cytology alone has not been reported. The initial clinical presentation is vague with prodromal phase of generalized malaise and these patients are often diagnosed as subacute meningitis of infectious or non-infectious etiology. Tuberculous meningitis is the main differential diagnosis and some receive anti-tuberculous treatment with no improvement.

All reported cases have been fatal and in the majority, the diagnoses were not suspected as

they were only made at postmortem examination (Chen et al. 1995 ; Rogers et al. 1995 ; Ng and Poon 1999 ; Corsten et al. 2001 ; Mathews et al. 2009 ) .

The few reported cases of “holocord” tumors have been found exclusively in children, ranging from 8 to 16 years. Initial clinical features include spinal deformities and bone changes. Neurological symptoms follow with gait clumsiness, paraes- thesias and tetraparesis, and eventually bladder and bowel impairment. Scoliosis may be the only sign of tumor for several years without other clinical signs. Tumors increase in size rapidly probably due to higher elasticity of bone and spinal cord in children (O’Brien et al. 1968 ; Pagni et al. 1991 ; Ushida et al. 1998 ) . Many children carry a history of orthopedic treatment until neurological decompensation supervenes.

Radiology

On plain X-ray of the spine, evidence of tumor may be seen as scalloping, erosion of pedicles and widening of the canal. In most cases, plain X-ray of the spine is normal. Myelography with positive contrast medium may show intramedullary as well as tumor of the fi lum, while intramedullary angiography is not helpful according to Fortuna et al. ( 1980 ) . Calcifi cation is best appreciated on CT. MRI is the procedure of choice in the investigation of spinal cord tumors. T1 weighted images may show hypointense cord enlargement, while T2 and FLAIR sequences are hyperintense, usually with perifocal edema. MRI of some tumors may show heterogenous features due to intratumoral hemorrhage and/or cystic degenera- tion as observed in T2 weighted MRI image in Fig. 7.1 (from Makuria et al. 2007 ) . Gadolinium enhancement has been associated with a less favorable prognosis (Reifenberger et al. 2007 ) .

In patients with PLO/PLG, the CT scan of the head may show hydrocephalus. In such patients, MRI with contrast may reveal enhancement and thickening of the leptomeninges throughout the brain and spine, often prominent over the basilar region. Brain or spinal cord intraparenchymal abnormalities are not observed. The MRI fi nding

of diffuse contrast enhancement resembles chronic meningitis and may be diffi cult to distinguish on images alone. Plain X-rays of patients with “holocord” oligodendroglioma reveal kyphoscoliosis.

Gadolinium-enhanced MRI may demonstrate the intramedullary mass, which may involve multiple segments of the cord in patients with “holocord”

oligodendrogliomas. Syringmyelia and syringo- bulbia may be seen in unaffected areas.

Pathology

Gross: The majority of spinal cord oligodendrogliomas are intramedullary, with ill-defined borders and a soft, gelatinous, consistency They often appear white or grayish-pink in color with a tendency to infi ltrate the meninges. A few examples are described as fi rm, reddish, circumscribed masses that were amenable to complete resection.

Fig. 7.1 T2 weighted sagittal MRI shows intramedullary mass in the thoracic spinal cord (C7 – T7) with heterogenous signal intensity and enhancement throughout the lesion (From Makuria et al. 2007 )

Some tumors are hemorrhagic and tumoral or peritumoral cysts may be observed. Anaplastic oligodendrogliomas have similar macroscopic features, but may demonstrate tumor necrosis.

Microscopy : Oligodendroglioma (grade II) is an infi ltrating glial neoplasm characterized by round, regular and monotonous nuclei that sometimes show cytoplasmic clearing or a “fried egg”

appearance. The even distribution and cytologic monotony are easily recognized at low magnifi cation (Fig. 7.2 ). Tumor cells are compartmen- talized by a delicate vascular arcade. Grade II tumors can show occasional mitoses, cytologic atypia, whereas marked mitotic activity, micro- vascular proliferation or necrosis is consistent with WHO grade III tumors. Cystic degenera- tion and microcalcifi cations, and myxoid areas

with occasional bizarre and enlarged nuclei are sometimes seen.

Although classic oligodendroglioma cells have clear cytoplasm, tumors may contain cells with eccentric eosinophilic cytoplasm resembling plump astrocytes referred to as minigemistocytes and gliofi brillary oligodendrocytes (GFO).

Microscopic examination of PLO/PLG shows the leptomeninges to be infi ltrated by small round cells with uniform nuclei and perinuclear haloes, sometimes accompanied by minigemistocytes.

In the case reported by Chen et al. ( 1995 ) although spinal leptomeninges were densely fi brotic intraspinal tumor cells were restricted to the subarachnoid space around the cauda equina and did not involve the spinal cord parenchyma.

Fig. 7.2 Representative morphologic features from formalin fi xed paraffi n embedded sections of an intramedullary oligodendroglioma from a 5 year old male. Lower magni fi cation shows monomorphic cells with clear cytoplasm

( a ) (hematoxylin and eosin, ×10). Higher magnifi cation of the clear cells ( b ) (hematoxylin and eosin, ×400). FISH analysis in this case demonstrated 1p36 ( c ) and 19q13 ( d ) co-deletion in the majority of the tumor cells (×1,000)

Immunohistochemistry

There are no specifi c immunohistochemical markers for oligodendroglioma. Furthermore, antigen expression between brain and spinal oligodendroglioma appears to be similar. In general, oligodendriogliomas express neuroectodermal markers such as S-100 and HNK1 (anti-Leu7, CD57). Although usually negative in classic oligodendroglioma cells, GFAP expression is observed in minigemistocytes and gliofi brillary oligodendrocytes, which may represent transi- tional forms between astrocytes and oligodendrocytes. Vimentin is expressed more often in anaplastic oligodendrogliomas. The survival rate

was low in cases with a MIB-1 index of more than 5% and usually corresponds with anaplastic features such as increased cellular pleomorphism and high MIB-1 index (Burger and Scheithauer 2007 ) . Classic tumor does not express neuronal markers synaptophysin, chromogranin, neurofi lament, neuron specifi c enolase, NeuN and basic myelin protein. In addition, cytokeratin, epithelial membrane antigen (EMA), vimentin, leukocyte common antigen and CD68 are negative in classic cases. Some cases may show evidence of neuronal differentiation with cytoplasmic expression of neuronal markers and even ganglion cells (Fig. 7.3 ). In these cases, demonstration of 1p/19q is crucial for distinguishing from central neurocytoma.

Fig. 7.3 Representative section of an intramedullary oligodendroglioma with neurocytic differentiation from a 33-year male. Lower magnifi cation shows monomorphic cells with clear cytoplasm as well as areas rich in astrocyte or ganglion-like cells ( a ) (hematoxylin and eosin, ×100).

By immunohistochemistry, there is heterogenous staining

for GFAP, clear cells being mostly negative ( b ), whereas there is expression of synaptophysin in clear cells ( c ). The ganglion-like cells are positive for chromogranin ( d ) (×100). This case had deletion of 1p36 in the majority of the tumor cells and deletion of 19q13 in some tumor cells

Molecular and Cytogenetic Findings In adult oligodendroglioma, approximately 80% of the cases contain the characteristic chromosome 1p36 and 19q13 co-deletion, due to unbalanced t(1,19) (q10; p10) translocation (Reifenberger et al. 2007 ) . Chromosome 1p/19q deletions have also been reported in spinal cord oligodendrogliomas and PLO/PLGs. Allelic loss of chromosome 1p alone occurs in 50–70% of low-grade and anaplastic tumors. This marker has become an important fi nding because it is associated with a favorable response to chemotherapy (Bauman et al. 2000 ) . Anaplastic oligodendrogliomas may additionally demonstrate losses of chromosome 9p, 10q, 19q, and uncommonly, TP53 gene mutations, although these alterations are not specifi c for oligodendrogliomas.

The genetic characterization can be obtained from three different techniques applied to paraffi n-embedded tissue: (1) comparative genomic hybridization (CGH), (2) fl uorescence in situ hybridization (FISH), and (3) polymerase chain reaction (PCR)-based microsatellite analysis for loss of heterozygocity (LOH) (Burger et al. 2001 ) . The FISH technique has the dual advantages of application on paraffi n-embedded tissue with access to tumor cytological and architectural features. Unlike LOH analysis, FISH does not require normal/constitutional DNA for the detection of deletions (Raghavan et al. 2003 ) .

Spinal cord oligodendrogliomas occur more frequently in children and young adults (Fortuna et al. 1980 ; Pagni et al. 1991 ; Ushida et al.

1998 ) . Unlike their adult counterparts, the cytogenetic and molecular profi le of pediatric oligodendroglioma is not well-characterized. In the pediatric age group, particularly in those who are less than 9 years, there is a paucity of both 1p and 19q deletions. On the other hand, older children and adolescents tend to have deletions of 1p and/or 19q. Thus, the molecular events that underlie the pathogenesis of oligodendroglioma in very young children requires further investigation.

Ultrastructural Findings

Only one example of spinal cord oligodendroglioma has been studied ultrastructurally and was found to share features similar to intracerebral cases (Garcia and Lemmi 1970 ) . The ultrastructural features of oligodendroglioma are characterized by the presence of round nuclei, scant cytoplasm with short processes and numerous microtubules. Although uncommon, pericellular spiral lamination of tumor cell processes is highly characteristic. Intermediate fi laments are absent in clear cells, but abundant fi laments are present within eosinophilic, astrocyte-like, GFAP positive cells. Rudimentary neuronal features including dense core granules and synapse-like junctions have been observed (Burger and Scheithauer 2007 ) .

Differential Diagnosis

There are a number of spinal cord neoplasms that mimic oligodendroglioma and may be challenging to distinguish, especially on a small biopsy speci- men. In some instances, the imaging features or previous history may provide helpful clues. The main differential diagnoses of spinal cord oligodendroglioma are clear cell ependymoma, central neurocytoma, clear cell meningioma, metastatic clear cell carcinoma and lymphoma.

Clear cell ependymoma: most cases of clear cell ependymoma occur in the supratentorial compartment, with rare cases reported in the spinal cord (Kim et al. 2007 ) . Microscopically, these tumors are circumscribed and usually lack the “chicken wire” pattern of blood vessels.

Perivascular pseudorosettes may be less conspic- uous in this variant, but when present, provide evidence of ependymal origin. Immuno histo- chemistry shows staining for GFAP, S-100, and vimentin, which may be seen in both entities.

Dot like cytoplasmic staining with EMA is a feature that differentiates ependymoma from oligodendroglioma. Desmin, neurofi lament, synaptophysin, chromogranin, keratin and p53 are negative.

Electron microscopy may show ependymal features such as intracytoplasmic lumen with or without microvilli lining (Kim et al. 2007 ) .

Central neurocytoma: neurocytoma may occur in the intramedullary compartment of the cervical or cervico-thoracic regions. Routine H&E stained sections typically show solid areas of uniform, polygonal cells and small round nuclei with delicate chromatin and perinuclear halos inter- rupted by neuropil islands. Similar to oligoden- drolioma, there may be chicken-wire vessels and foci of minigemistocytes. Large cells with round nuclei and eosinophilic cytoplasm suggest gangli- onic differentiation. Mitoses and necrosis are rare.

Electron microscopy shows evidence of neuronal differentiation with cytoplasmic processes fi lled with tubules, synaptic vesicles, and dense core granules. Immuno histo chemical preparations demonstrate reactivity with neuronal markers such as NSE, neurofi lament, synaptophysin. With the exception of reactive astrocytes, tumors lack GFAP staining. Rare cases of oligodendroglioma with synaptophysin reactivity have been reported (Makuria et al. 2007 ) . In controversial cases, analysis of chromosome 1p/19q deletions should be performed to confi rm the diagnosis.

Clear cell meningioma: in contrast to oligodendroglioma, clear cell meningioma shows pronounced vascular collagen and glycogen-rich cytoplasm with diastase-sensitive PAS reactivity and immunoreactivity for EMA.

Metastatic clear cell carcinoma: distant metastasis from clear cell tumors, particularly clear cell renal cell carcinoma, may mimic oligodendroglioma. However, sharp tumor borders and immunoreactivity for cytokeratin and EMA will assist in differentiating the two tumors in concert with appropriate clinical history.

Malignant Lymphoma: lymphoma may rarely show diagnostic overlap with oligodendroglioma, but is usually positive for lymphoid and B-cell markers (CD45, CD20, Pax5).

Summary

Accurate diagnosis of spinal cord oligodendroglioma and further molecular characterization is crucial, because overall survival and response to

treatment has been found to be favorable for patients with this tumor (Guppy et al. 2009 ) . Classic low-grade oligodendrogliomas are classifi ed as Grade II tumors and anaplastic oligodendrogliomas as Grade III according to WHO classifi cation of tumors of the central nervous system (Reifenberger et al. 2007 ) . The association between classic oligodendroglial phenotype and combined 1p and 19q loss has been shown to have biological signifi cance and diagnostic utility.

More specifi cally, patients with these tumors are more likely to respond to chemotherapies than patients with astroglial tumors of comparable grade.

In their review of molecular subtypes of anaplastic oligodendroglioma, Ino et al. ( 2001 ) demonstrated that patients with anaplastic oligodendrogliomas, and combined allelic losses of 1p and 19q (group 1) had a uniformly excellent prognosis with a durable response to chemotherapy.

Patients harboring other 1p losses (group 2) or TP53 mutations (group 3) had an intermediate prognosis with limited response to chemotherapy.

Finally, patients without 1p loss and TP53 muta- tion (group 4) experienced a uniformly poor outcome, seldom responding to chemotherapy.

This prognostic stratifi cation on the basis of 1p19q status underscores the importance of molecular diagnosis in the clinical management of patients with anaplastic oligodendrogliomas.

Although the association of loss of 1p/19q augurs a more favorable response to chemotherapy in adults, Pollack et al. ( 2003 ) did not describe a survival advantage in pediatric gliomas with 1p/19q deletions. Since 1p/19q deletions are rare in pediatric population, 1p/19q deletions cannot be used as a molecular marker for oligodendroglioma in children. Further investigation is warranted to identify reliable molecular markers for the diagnosis of childhood spinal cord oligodendroglioma.

References

Bauman GS, Ino Y, Ueki K, Zlatescu MC, Fisher BJ, Macdonald DR, Stitt L, Louis DN, Cairncross JG (2000) Allelic loss of chromosome 1p and radiotherapy plus chemotherapy in patients with oligodendrogliomas.

Int J Radiat Oncol Biol Phys 48(3):825–830

Dalam dokumen Tumors of the Central Nervous System Volume 6 (Halaman 76-85)