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We report two new cases of chordoid glioma of the third ventricle and review all previously published cases of this rare tumor with regard to presentation, optimum management, and outcome. Two new cases are reported with the radiological and histopathologic findings. We searched and cross-referenced PubMed and published reports of this tumor to retrieve an additional 51 cases of this tumor, which were then analyzed according to a proforma. Chordoid glioma has consistent radiological features, although some atypical elements including a cystic component are well described. The insidious presentation and morbidity of attempted surgical resection combine to give high overall morbidity. There is a high incidence of postoperative thromboembolic disturbance. Adjuvant radiosurgery has a promising role. The morbidity of this condition is likely to remain high but may be minimized by a less aggressive surgical approach together with surveillance and early use of radiosurgery.
Chordoid glioma (CG) is an unusual, slow-growing, noninvasive primary neuroepithelial central nervous system (CNS) neoplasm of uncertain origin, classified by the World Health Organization in 2000. It was first named by Brat et al in 1998, although its features were first described by Wanschitz et al in 1995 in a 24-year-old woman.1,2 Clinical presentation varies. Headache, amnesia, and visual disturbance are common features. Focal cortical deficits are relatively rare.3 The delay from onset of symptoms to diagnosis is highly variable.
Differential diagnoses include tumors affecting the suprasellar region: meningioma, ependymoma, pilocytic astrocytoma, chordoma, and lymphoma.1,4,5,6 Radiological isodensity may lead to suspicion of an unruptured aneurysm or lymphoma.4,5,7 Craniopharyngioma may be suspected due to a cystic component.8 Nonfunctioning pituitary tumors may be suspected, although on magnetic resonance imaging (MRI), CG should be distinct from pituitary gland and stalk.4 Inflammatory lesions such as neurosarcoid and histiocytosis may be suspected.4,5
Radiological features of CG are remarkably consistent, although the exact site of origin can be difficult to identify.1,7 CG typically appears as a third ventricular or suprasellar mass often extending into the hypothalamus, isointense on T1-weighted MRI with strong uniform contrast enhancement.7,8 CG is well defined and usually has an ovoid shape, with greatest diameter in the craniocaudal direction.9 CG can produce obstructive hydrocephalus; development depends more on tumor location than size.7 Calcification is rare. CG may have a cystic component.7 Vasogenic edema may impinge on the optic apparatus.7 The tumor may be large at the time of diagnosis.8
The surgical findings vary, from tumors with a plane allowing easier tumor dissection to close adherence to the optic apparatus and hypothalamus.4,10,11 Few defining macroscopic features are described, but it is frequently attached to the lamina terminalis with a uniform gray or brownish color and variable consistency.12
Histopathologic findings are variable although glial fibrillary acidic protein (GFAP) CD34, and vimentin positivity suggest glial origin from tanycytes, a subgroup of ependymal cells, possibly of embryonic origin. The midline location may favor an embryological origin.13 CG has low mitotic activity (MIB-1 and Ki67 values below 5%). Ultrastructural features include intermediate junctions, intermediate filaments, microvilli-like projections, and focal basement membrane. CG is negative for p53 and other key tumor suppressor and proto-oncogenes, as well as genetic markers of other CNS tumors, such as TP53, EGFR, CDK4, and MDM2 genes.14 It is also negative for estrogen and progesterone receptors, unlike intermediate- and high-grade gliomas.6,15
We present two new cases of CG, one with unique histopathologic features. We review all previously reported cases of CG focusing on clinical and surgical aspects. We also review radiological and histopathologic findings and discuss the evidence for optimum management of this rare tumor.
A 48-year-old woman presented with 5 months of fluctuating visual failure and progressive intermittent headaches. Examination found left optic pallor but normal visual fields. There was no history of endocrine or memory disturbance. MRI showed a 2-cm round, homogenously enhancing, well-defined lesion adjacent to the floor of the third ventricle, with compression of the optic chiasm from above with little surrounding edema (Fig. 1). The presumed diagnosis was of an intraventricular meningioma.
A bifrontal craniotomy and interhemispheric approach to the tumor was performed, and the tumor was debulked extensively. A poor plane was established superiorly and posteriorly between the tumor and brain, and resection was incomplete.
Histopathology showed a tumor with low mitotic proliferation and clusters of ovoid epithelial cells with eosinophilic cytoplasm and mucinous stroma. The tumor was positive for GFAP, CD-34, S-100, and vimentin. The diagnosis was of CG.
Postoperatively, the patient developed severe electrolyte disturbance with alternating diabetes insipidus and syndrome of inappropriate antidiuretic hormone secretion. She also suffered prolonged confabulatory amnesia. After 3 months, her electrolyte imbalances settled. She underwent follow-up MRI at 6 months and 1 year, showing stable residual disease (Fig. 2).
A 36-year-old man presented with a 1-week history of worsening headache and a 1-year history of polyuria and polydipsia. Neurological and ophthalmologic examinations were unremarkable. Endocrine studies showed hypothalamic dysfunction. MRI showed a well-defined, solid suprasellar mass, suspicious of craniopharyngioma. Total resection was achieved via bifrontal craniotomy and translamina terminalis approach. No adjuvant therapy was given. The early postoperative course was eventful with diabetes insipidus, metabolic myopathy, diencephalic amnesia, partial hypopituitarism, and hypothalamic syndrome with weight gain. At 40 months of follow-up, the patient continues to suffer intrusive amnesia and hypopituitarism. Further MRI scans have shown no evidence of recurrence.
The tumor was built up by cords, files, and clusters of epithelioid tumor cells with abundant eosinophilic cytoplasm and separated by dense, collagen-rich fibrous stroma and infiltrated by large numbers of lymphoplasmacytic cells (Fig. 3). Numerous Russell bodies were noted in plasma cells. There was only little mucin deposition in the stroma. Focal microcalcification was also noted. Mitotic figures, vascular proliferation, and necrosis were absent. In the adjacent atrophic, non-neoplastic brain tissue, reactive astrocytes, and Rosenthal fibers were seen. GFAP immunohistochemistry showed strong cytoplasm staining and highlighted the multipolar fibrillary processes of the tumor cells, although some tumor cells remained negative. CD34 was strongly positive in all tumor cells. EMA, MNF116, chromogranin, and synaptophysin were negative. The inflammatory cells revealed a mixture of CD20-positive B cells, CD68 (PGM1)-positive macrophages, and some CD3-positive T cells. Ki67 was expressed in less than 1% of the tumor cell population.
The features were consistent with a CG of the third ventricle, although the prominent desmoplasia and the lack of mucinous stroma were highly unusual.
Fifty-three cases of CG have been reported to date, including the presented cases. Their details according to our analysis are presented in Tables Tables11 and and2.2. Nineteen cases (36%) occurred in male patients and 34 (64%) in female patients. Only three pediatric cases (5.7% of the total) are reported, in two boys and one girl aged 5, 12, and 7, respectively. Ages range from 5 to 71 years.
Clinical presentation was described in 50 cases, most commonly headache (20 patients, 40%) and visual disturbance (15 cases, 30%). Twelve patients (24%) reported memory deficits (summarized in Table Table33).
Six patients (12%) presented with endocrine symptoms. Other symptoms reported include sweating, gastrointestinal disturbance, speech dysfunction, and sleep apnea.
Thirty-nine patients (78%) were polysymptomatic. Eleven cases (22%) were clearly monosymptomatic, with visual disturbance being the most common sole symptom in these cases.
The timescale of clinical presentations was described in 39 cases. Twenty-nine cases (74%) presented chronically, 5 (13%) presented acutely, and 5 (13%) manifested in an acute-on-chronic manner. The duration of chronic symptoms was a few weeks to 20 years.
Twelve of 32 patients (37.5%) had a visual field defect. Visual acuity was reported as abnormal in six cases (19%). Two patients (6%) had optic neuropathy, two patients (6%) had other visual signs, and one patient (3%) had papilledema. In total, 23 out of 32 patients (72%) displayed visual signs. Seven cases (22%) showed endocrine dysfunction, mainly affecting the sex hormones. Seven patients (22%) had a focal neurological deficit.
Thirty of 53 cases conformed to the typical radiological description of CG: a solid, well-defined, ovoid, isointense suprasellar/third ventricular mass with strong uniform contrast enhancement. Unusual radiological features are summarized in Table Table4.4. One tumor was sited in the temporoparietal region, another in the corona radiata and thalamus. Both were pediatric cases. One of the pediatric cases also exhibited hemorrhage within the tumor. Seven cases (13%) had radiological evidence of hydrocephalus. The largest tumor, a pediatric case, measured 7×5.5×4 cm. The smallest was 1.5 cm in diameter.
Forty-nine of 52 cases (94%) were debulked or removed completely. Eleven cases (21%) were biopsied. In 3 (6%) of these 11 cases, biopsy was the only management used without resection. Nine (17%) patients received adjuvant radiotherapy: external beam in three, radiosurgery in four, and radioactive implants in two. Shunting was required in 5 (9.6%) patients.
Details of the surgical approach used are available for 26 patients. Four cases (15%) were managed by the transcallosal approach and 5 (19%) by the translamina terminalis approach. Three tumors (11.5%) were approached interhemispherically (no further details) and 3 (11.5%) by a transventricular route. A subfrontal approach was taken in two cases (8%). Unspecified bifrontal craniotomy, anterior approach, and transsphenoidal routes, respectively, were taken in one patient each.
The extent of resection was reported in 44 patients. Two patients required more than one resection, making a total of 46 resections. Twenty-four out of the 46 resections (52%) were reported total and the remaining 22 (48%), subtotal. Of the subtotal and partial resections (22 operations), eight received adjuvant radiotherapy and 14 did not. Twenty-one patients of the 44 reported were left with residual tumor following surgery.
Postoperative complications were discussed in 39 cases. Table Table55 shows the frequency of the most common complications. As expected, these relate to the presenting symptoms and location, with hypothalamic disturbance and amnesia being most common.
Data on outcome are variably reported. The range of follow-up is 0 to 68 months in living patients and one postmortem report in a patient who died of unrelated causes 6 years later. Visual improvement was noted in four patients. No new neurological deficit was reported in nine cases. Formal functional assessments are seldom available.
There were 15 deaths. One-third of these were due to pulmonary embolism. Four deaths (27%) were caused by infection. Two patients (13%) had a cardiac arrest. Two deaths (13%) were considered directly attributable to tumor. Two-thirds of the 15 deaths occurred in the first 4 weeks postoperatively.
Little follow-up data are reported. Recurrence was noted in one patient following an apparently total resection. Progression was noted in 5 of the 22 cases where subtotal resection was performed. Following total resection, no recurrence has been found in 15 patients. Twelve patients remain progression free after a subtotal or partial resection.
Of the nine patients receiving adjuvant radiotherapy, progression was observed in three. All these patients had received conventional radiotherapy following an incomplete resection. One patient received both conventional radiotherapy and radiosurgery after an incomplete resection with no subsequent recurrence. Three patients received gamma knife treatment following an incomplete resection and none showed progression. Two patients had radioactive implants. One of these patients remains recurrence free and the other died of unspecified causes in the early postoperative period.
Table Table66 shows the immunochemical patterns observed.
All 50 cases that were histologically analyzed exhibited the typical cord and clusters of polygonal epithelioid cells. Twenty-nine cases were observed for Russell bodies and were present in 28 (97%). Twenty-seven cases showed round-oval nuclei. Thirty-six out of 36 cases had eosinophilic granules or cytoplasm. The stroma of 49 cases was described as mucinous or myxoid and in all, although sparse in a few cases and very sparse in the second present case. Reactive gliosis or Rosenthal fibers were found in 14 of 16 cases (88%). Lymphocytic and plasma cell infiltrates were present in 48 of 50 cases (96%), albeit sparsely in 5 (10%). Significant mitoses were only found in 1 of the 45 cases. Necrosis was present in the same case and was looked for in 28 cases. The MIB-1 was recorded in 17 cases with a mean value less than 5%. Ki67 was recorded in 22 cases and ranged from 0.3 to 5%.
CG occurs mainly in adults, with only 3 of 53 cases in pediatric age group.10,16,17 A female-to-male ratio of 2 to 3:1 has been described, similar to our findings of ~3:2.4,6 CG has no known risk factors or syndromic associations and no etiologic factor could be identified in this review. One case had coexisting Rathke's cyst, probably unrelated.15
CG typically arises in the suprasellar region and the third ventricle, with all but two of the cases reported arising in these structures, supporting embryological origin. CG can extend to occupy the entire ventricle, suprasellar, and hypothalamic regions.
CG rarely arises elsewhere, with no reports of this in adults and only two cases overall. In one, CG arose from the left temporoparietal cortex in a 5-year-old boy and in another from the corona radiata and thalamus in a 7-year-old girl.10,16 The cystic component of one tumor invaded the right temporal lobe of a 70-year-old man, but did not originate here.1 The unusual site of CG at the extremes of age may be relevant. The pediatric cases were atypical in other aspects and are considered later. Metastasis is not described.
Overall, chronic presentations predominate (months to 20 years, with 6 months to 2 years being the most common), occurring in almost 75%. Although CG is described as slow growing, rapid periods of growth are reported in one case where tumor remained stable for 3 years and then underwent a sixfold expansion over 6 months.5 This may create an acute on chronic mode of presentation, mistaken for hemorrhage within a tumor or misdiagnosed as another more typically aggressive tumor.
CG frequently presents with multiple nonspecific symptoms (39 cases) rather than with one presenting feature (11 cases), probably due to location. Endocrine presentations are uncommon, occurring in only six cases. Memory impairment, occurring in 12 patients, is more site specific, and combined with radiological factors may be sufficient to include CG on the list of differential diagnoses. Visual field deficit is the most common abnormality on examination. Ophthalmic assessment should therefore be thorough and may be used for monitoring purposes.
Only 32 of the 53 cases were radiologically typical for CG: midline in the third ventricle, well circumscribed, round or ovoid, and uniformly enhancing. The most common atypical feature was a cystic component, present in 14 cases. The rarity of hemorrhage within CG (two cases) may be testimony to its slow-growing nature.
Experience is limited to two cases: one a 71-year-old woman presenting with chronic visual failure.18 The patient received only serial visual field monitoring, which did not change. Follow-up duration is not specified. The second, a 37-year-old woman, was managed by shunt, biopsy, and radioactive implants for 9 months before interval MRI showed considerable extension necessitating surgery.6 A conservative approach to this tumor may therefore only be considered in asymptomatic or minimally symptomatic patients, and given reported periods of rapid tumor enlargement, this strategy is likely to have an appreciable failure rate. Periods of rapid growth in tumors under surveillance may be more common in female patients.5,6,19
Surgical approaches are typically midline. Subfrontal translamina terminalis approaches offer excellent chiasmal exposure with lesser access to the superior components of the tumor. For tumors with a large intraventricular component, a transcallosal or transcortical transventricular approach may be used, especially in the presence of preoperative hydrocephalus. The transsphenoidal approach has been used once; we suspect that it would be unlikely to offer appropriate access for such a tumor, especially given the propensity for CG not to cause sellar expansion. Pterional craniotomy has been used to approach lateralized CG, but achieving major resection with this approach is very challenging. There will surely be a future role for endoscope-assisted resection of the tumor in the third ventricle.
Ventricular drainage has been used infrequently. It was not associated with infection in the five patients who were subsequently shunted.
Postoperative complications following resection of CG are common with only seven patients following an uneventful postoperative course. There is little information available on performance status following treatment. The commonest outcome measures are absence of new neurological deficit, visual improvement, and death.
Venous thromboembolism prophylaxis and recognition are vital as CG appears to be associated with a high rate of thrombotic complications postoperatively, especially fatal pulmonary embolism.
Postoperative hypothalamic-pituitary-axis disturbance is frequent and may be severe. Diabetes insipidus, typically transient, was the most common. Amnesia (a common presenting symptom) was the next most common postoperative complication, occurring in 10 of the 39 cases that reported complications.
Death is most likely to occur in the first month postoperatively, with 10 out of 15 deaths in this period. This number includes deaths from pulmonary embolism and cardiovascular causes, which if ignored, make death in the first month postoperatively unlikely.
Adjuvant radiotherapy has been used following subtotal resection.1 The type of radiotherapy given is associated with recurrence risk. Iwami et al discuss the promising role of adjuvant gamma knife radiosurgery as it was not associated with recurrence in the three patients who received it.20 External beam radiotherapy, however, was associated with recurrence in all three patients treated. Nakajima et al used gamma knife as an adjuvant after resecting only 70% of the tumor mass, finding stable residuum at 3.5-year follow-up.21 More experience is required with postoperative radiosurgery to establish if it should routinely follow subtotal resection to minimize recurrence. Using adjuvant radiosurgery may reduce the need for aggressive resection and the attendant morbidity. The efficacy of radioactive implants is not established. It has been attempted on two patients, one of whom had no recurrence and one of whom died of sepsis in the early postoperative period. There is no report of adjuvant chemotherapy.
Progression following incomplete removal was recorded in five cases. Recurrence was rare following total macroscopic resection, occurring once in 24 cases, with maximum follow-up available 68 months. Early recurrence is reported: Jung and Jung report recurrence in a 50-year-old woman who underwent subtotal resection via the transcallosal approach. Recurrence occurred 3 months postoperatively, and the patient died a month later after no further intervention.11 One of Brat's cases showed recurrence within the residual tumor at 5 months and death at 8 months of unrelated causes in a 47-year-old woman.1 Late recurrence has also been described, occurring 3 years following subtotal resection and adjuvant external beam radiotherapy.1 This CG was found at postmortem to fill the entire third ventricle, again supporting the observation of rapid growth periods in women. Another patient, who received external beam radiotherapy following subtotal resection, showed small and asymptomatic recurrence at 4 years.
Reoperation for recurrence is little described. Hanbali et al performed subtotal resection and radiotherapy for CG.22 The patient represented 1 year later and underwent a second operation where total resection was achieved. The patient died after 3 months from myocardial infarction. Reoperation for raised intracranial pressure was performed 5 days after the first operation in a 36-year-old man, with no detailed discussion of outcome.8 From the cases of aggressive recurrence and rapid growth presented, cautious reoperation in the context of recurrence or progression is probably advisable with adjunctive radiotherapy or radiosurgery. No factors, other than incomplete resection and possibly use of conventional rather than gamma knife adjuvant radiosurgery, predisposing to recurrence could be found from our review.
Only three pediatric cases have been described and all have unique clinicopathologic features, summarized in Table Table8.8. It is difficult to comment on the long-term outcome of CG in children. One child died 2 days postoperatively from a cardiac arrest.16 However, the tumor may be more aggressive in children, manifest by the acute presentations, short history, hemorrhage within the tumor, and large size.16
The treatment-related morbidity of CG is very high. Outcomes will only be improved by better preoperative recognition of this tumor entity, allowing a more cautious approach to definitive surgery. A low threshold should be maintained for the use of radiosurgery in the context of subtotal removal or early recurrence.