Management in chordoid glioma: Avoiding the pitfalls in this rare and challenging entity
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/neuroindia.NI_1008_15
Source of Support: None, Conflict of Interest: None
Keywords: BRAF, chordoid glioma, minimally invasive, mortality, radiosurgery, third ventricle
Chordoid glioma (CG) of the third ventricle is an unusual, benign, and slow growing neoplasm, with a probable origin in the ependyma. In 1998, Brat et al., established the main pathological features of this neoplasm. Due to its low incidence, CG is not usually suspected and its prognosis and appropriate treatment remain unknown. In this article, we present a case of CG located in the anterior third ventricular region, emphasizing the treatment related morbidity and mortality. Based on the available literature, we review the clinical settings and diagnostic approaches related to CG, discuss the histological features and differential diagnosis, and critically assess the current status of its clinical and surgical management.
The case concerns a 46-year old women suffering from restless leg syndrome. She had hypothyroidism that was diagnosed 2 years prior to the development of her intraventricular tumor and she was on a regular thyroxine replacement therapy. The patient complained of amenorrhoea and a progressive decrease in the visual acuity and libido. The physical examination revealed an inferior bitemporal quadrantanopsia.
The magnetic resonance image (MRI) revealed a suprasellar (31 mm diameter) solid mass, with a small caudal cystic component. Being of heterogeneous intensity on T2 sequence, the tumor showed a prominent enhancement after the administration of gadolinium. Although a clear mass effect and moderate edema reaching up to the internal capsule and the mesencephalon were demonstrable, no hypervascularity or parenchymatous infiltration were observed on the MRI scan. As a result, the optic chiasma was pushed downwards and the anterior wall of the third ventricle, subthalamus, and mesencephalon were displaced [Figure 1]. The main presurgical diagnosis was a meningioma. The other diagnoses that were considered included a craniopharyngioma, subependymoma, choristoma, or pilocytic astrocytoma. Surgical treatment was performed through a supraorbital subfrontal approach. A solid pearly white-appearing mass was detected. The assistance of an intraoperative MRI and neuronavigation were also taken during surgical excision of the lesion. The lesion was partially debulked with ultrasonic aspiration, and the pathological samples was harvested. Complete capsular dissection could not be performed as it was strongly adherent to the surrounding structures due to which the patient developed bradycardia during its attempted removal. Intraoperative MRI confirmed the persistence of three quarters of the volume of the initial mass on the posterior and superior margins of the tumor. Despite the presence of residual tumor, due to life-threatening intraoperative incidents during the dissection, the surgery was interrupted at this point. Postoperative MRI revealed a partial resection (30%) of the most anterior part of the tumor.
The histological evaluation revealed a cord and cluster-forming epithelioid cell neoplasia, admixed in a myxoid and focally fibrous stroma [Figure 2]a,[Figure 2]b,[Figure 2]c. Ancillary immunohistochemical studies revealed marked positivity for glial fibrillary acidic protein (GFAP) [Figure 2]d and vimentin, as well as cluster of differentiation (CD) 34, with focal positivity for S-100 protein. Other neuronal, germinal, and epithelial markers (including thyroid transcription factor 1 [TTF1]) were negative. The proliferative index assessed with MIB-1 antibody (Ki67) ranged from 1–5%, with the highest values corresponding to the region having focal inflammatory infiltrates [Figure 2]e. Consequently, the tumor was diagnosed as a CG of the third ventricle (grade II of the World Health Organization [WHO] classification). BRAF V600E [v-Raf murine sarcoma viral oncogene homolog B1] mutation was evaluated through deoxyribonucleic acid (DNA) extraction from formalin fixed-paraffin embedded tissue, and subjected to polymerase chain reaction (PCR) amplification of BRAF exon 15, and posterior Sanger sequencing. The tumor was identified as wild type.
No immediate surgical complication was detected; 72 hours after the surgery, a clinical picture of progressive disorientation, memory loss, and psychomotor agitation occurred. On the 5th postoperative day, with previous normal blood tests, a severe hyponatremia (110 mEq/L) suddenly set in. A hormonal study revealed panhypopituitarism. The patient recovered without any long-term sequelae after being transferred to the intensive care unit and treated with hypertonic solution, desmopressin, fludrocortisone, and increased dosage of levothyroxin. The patient was discharged with the ophtalmological tests showing a mild persisting inferior bitemporal quadrantanopsia.
The neurooncology committee recommended a watchful follow-up with a new MRI scan to be done at 6 months. No adjuvant therapies were considered due to the absence of scientific evidence of their effectiveness.
An increase in the volume of the mass was evident on the MRI that was performed after 6 months, in comparison to the immediate postsurgical MRI [Figure 3].
The patient underwent a second surgery. This time, an interhemispheric transcallosal approach was chosen. During the procedure, there were signs of hypothalamic involvement, mainly manifesting as significant bradycardia. Gross total resection was achieved [Figure 4]a. The resected specimen revealed identical histological features as the previous resection. The tumor presented with foci of hemorrhagic, ischemic, and fibrous changes, along with focal calcium deposits, attributable to the previous interventions. The patient unfortunately suffered from a hypothalamic injury during her resurgery [Figure 4]b, which resulted in a refractory coma and cardiovascular instability leading to her death 10 days after the second surgery.
Chordoid glioma: Clinical setting
The CG is a pathologic entity that has been recently characterized. In 1995, Wanschitz et al., were the first authors who described the histopathological features of the CG of the third ventricle. They considered it to be a peculiar variation of a suprasellar meningioma with glial fibrillary acidic protein (GFAP) expression. In 1998, Brat et al., characterized it as a distinct clinical pathology. The origin of CG remains unclear, though some light has been shed in the last few years. Electron microscopy suggests a glial origin, specifically from ependymal cells known as tanycytes. These cells are located in the anterior third ventricle, covering the organum vasculosum of the lamina terminalis and the subforniceal organ. Thyroid transcription factor-1 (TTF-1) expression has been noted in CG supporting the hypothesis that places the origin of this tumor in the vicinity of organum vasculosum.
After the publication of the first series in 2011 by Liu et al., there have been approximately 85 cases reported where this rare pathology has been described. Despite the small number of cases reported, it is known that it affects women more than men (2:1), around the age of 45 years. As an exception to the general rule of this tumor predominating in middle aged women, there is evidence of this tumor also occurring in 4 children.,,, Our patient represents the most common epidemiological pattern; however, there are some unusual elements in our case that may be worth noting. Although the diagnosis is often incidental (in 20% of the cases described in literature), our patient had mild visual (seen in approximately 30% of the reported patients) and endocrinological (amenorrhoea, reported in approximately 6% of patients) symptoms.
Diagnostic approach: A radiologic basis
The radiological study is fundamental for the diagnostic and therapeutic approach to the CG. Computed tomography (CT) is usually the first investigation to be performed. On the CT scan images, a CG appears as an iso- or hypodense mass with homogeneous enhancement after the administration of iodinated contrast. However, the ideal radiological investigation is a magnetic resonance imaging (MRI) scan [T1 and T2-weighted images with gadolinium administration]. The CG is usually a well-defined, isointense, oval or round shaped tumor, mainly located in the anterior part of the third ventricle, in close relation with the hypothalamus, with an avid and homogeneous contrast enhancement. Sometimes, it is possible to observe a cystic component in the periphery of the lesion (seen in 26% patients), as was observed in the inferior region of the tumor in our patient [Figure 1]c and [Figure 1]d There is only one case described in which this cystic component turned out to be an associated Rathke cleft cyst. Heterogeneous enhancement, calcification, and signs of hemorrhage are less common symptoms (observed in approximately 4-6% patients) seen in the adult population. However, it is more frequent to observe atypical radiological signs and unusual locations in the paediatric population; these include the left temporoparietal region  or the location next to the right lateral ventricle extending to the thalamus. Considering its slow growth rate, intratumoral hemorrhage is an infrequent phenomenon. CG may cause chiasmal compression with edema occurring along the optical tracts or extending over the cerebral peduncles, as was seen in our patient. However, there is only one reported case where optic chiasmal infiltration occurred. The magnetic resonance spectroscopy (MRS) of the CG, that has been recently described, mimics the findings of a low grade tumor.
Histology: An idiosyncratic pattern
Pathologic evaluation enables the definitive diagnosis of CG. The CG is defined as an epithelioid cell neoplasia arranged in cohesive cords, ribbons, or clusters, with a finely collagenized stroma and a basophilic matrix with a mucinous appearance., Cells have oval –to-polygonal shapes with well-defined irregular borders, an eosinophilic cytoplasm, and round-to-oval nuclei with small inconspicuous nucleoli. The tumor has a distinct reactive lymphoplasmacytic infiltrate, with occasional Russell bodies. Evident nuclear atypia, mitosis, necrosis, or vascular proliferation have not been observed. The tumors have sharply demarcated borders, with reactive gliosis and occasional Rosenthal fibers in the surrounding brain parenchyma. Immunohistochemical studies usually show a positivity for GFAP and vimentin,, as well as variable positivity for CD34 (88%), S-100 (75%), cytokeratin (71%), and epithelial membrane antigen (EMA) [67%]. Neuronal markers, such as synaptophysin or neurofilaments, can be positive in up to 20% of the cases. D2-40, a monoclonal antibody, can serve as an adequate additional marker for CG because cases with focal and intense positivity have been reported.
The CGs have a broad radiological as well as histological differential diagnosis. The chordoid pattern with a myxoid background may occur in a chordoma, and is very similar to the architecture found in other tumors found in a similar location such as the chordoid meningioma (a World Health Organisation grade I tumor), and can even simulate the histological findings of a pituitary adenoma. In addition, intratumoral inflammatory infiltrates are usually present in germ-cell tumors, frequently in midline regions of the brain, and are also an important component of the lymphocytic meningioma. Other frequently encountered lesions of the anterior third ventricle are craniopharyngiomas, meningiomas, ependymomas, hypothalamic gliomas and hamartomas, germ-cell tumours, colloid cysts, choroid plexus papillomas, and central neurocytomas. However, most of these entitites are histologically distinct from a CG and, therefore, do not represent a diagnostic challenge when being differentiated from a CG. Nevertheless, the confirmation of the glial nature of the CG is mandatory along with the employment of an adequate immunohistochemical panel to differentiate the entity from other tumors with a similar morphological spectrum. A proper differential diagnosis is critical because the CG may have a variable histological appearance and may present with an overt epithelioid appearance with the presence of cell cords, papillae or pseudoglands., This histological feature may occasionally even lead to an erroneous diagnosis of a metastatic carcinoma
Management: A complex framework
Surgery is the mainstay of the treatment of CG. In the cases described in the literature, 5 patients underwent a biopsy, 34 underwent a partial resection (PR), 34 underwent a complete resection (CR), one was treated exclusively using radiosurgery, and information regarding the intervention performed was missing in the remaining 11 cases. The optimal treatment for the CG is complete resection because, according to the literature reviewed, the lesion once it is completely resected is not associated with a recurrence. However, the associated postsurgical mortality (19%) and morbidity (67%) rates following complete resection are remarkable. PR with adjuvant treatment provides better results with regard to both mortality (14%) and morbidity (50%) at the expense of a higher recurrence rate (28%). We carried out a statistical analysis based on literature data using Pearson's chi-square test (χ2). We did not find a significant relation between the extent of resection and mortality (P = 0.22). A greater number of cases, a uniform assessment of the variables, and a longer follow-up period could provide more insightful results.
There are several approaches to reach the anterior wall of the third ventricle. The safest way based on the results of the interventions performed in the CG cases described so far include the trans-lamina terminalis approach, the transcallosal approach and the transventricular approach. We describe the supraorbital, subfrontal translamina terminalis, approach, with the skin incision in the ipsilateral eyebrow, a minimally invasive surgery that offers a good access to the affected region with a minimal frontal retraction and practically no cosmetic defect. Although this surgical corridor provides an optimal approach to the lesion, the extent of resection might be limited by the tumoral adherence to the surrounding critical neural tissue.
The most frequent postsurgical complications are diabetes insipidus (20%), cognitive disorders (15%), and pulmonary embolism (9%). Our patient presented with significant hyponatremia, with the serum sodium levels reaching 110 mEq/ml. In addition, she also presented with important neuropsychological signs such as disorientation, amnesia, and psychomotor agitation. She also developed panhypopituitarism with the most significant manifestation being hypothyroidism. Overall, during resection of a CG, adequate emphasis must be paid on defining its relationship with the hypothalamic structures in close proximity to avoid serious postoperative complications.
The apparently benign character of this neoplasm contrasts with the high morbidity and mortality rates that have occurred following administration of standard treatment for it. Considering the young age of the affected group, the vital neuroendocrinological structures involved, and the benign nature of this lesion, it is evident that an aggressive attitude should be discarded and a more conservative approach be adopted. Even in the patients in whom complete resection has not been possible, rather than aggressively conducting a second surgery to perform an in toto resection of the tumor, other adjuvant therapies could be pursued, that may lead to a better result for the patient.
In general, the use of adjuvant therapy for the treatment of CG has been controversial. There is no reference to the use of chemotherapy as part of the treatment for CG. However, radiotherapy (RT) and radiosurgery have often been used [Table 1]. Radiosurgery, mainly gamma knife radiosurgery, seems to be a good therapeutic option as neither tumoral recurrence nor progression have been observed in the follow-up period in any of the cases where radiosurgery was used after a partial resection or a biopsy. However, all of those cases who were treated with external or interstitial RT presented with recurrence. Considering the small number of cases and the insufficient and heterogeneous information provided, there is not enough evidence to advocate RT as an adjuvant treatment in the cases of subtotal resection. No references to the use of prophylactic RT after a CR were found.
Among the eight cases where recurrence was reported following the first surgery in literature, three were treated with resurgery, 1 was placed under observation, and information regarding further treatment administered was not available in the remaining 4 patients. Resurgery for recurrent tumors was associated with a higher resection rate but also with a poorer clinical result. In the case reported by Hanbali et al., after an initial partial resection followed by adjuvant RT, the tumor recurred during the 7th month, and a CR was achieved in the second surgery. Two months after this second major surgery, the patient died at the age of 57 years due to a massive myocardial infarction. In the patient reported by Kurian et al., after a biopsy and interstitial radiotherapy with iridium 192 seeds, the patient (aged 37 years) underwent a second surgery due to the recurrence of the tumor after 9 months. Two weeks after a maximum partial resection, she died of sepsis. In the patient reported by Nga et al., the patient (aged 49 years) was initially treated with radiosurgery. After the tumor had remained stable for 6 years, it started regrowing. A gross total resection was achieved during the second surgery; however, the patient died 18 days later due to pneumonia. All these cases illustrate the challenges faced during the treatment of symptomatic recurrences in the case of CG. Our patient also faced the same challenges. A patient who is minimally symptomatic (as was observed in our case) and has a slow growing lesion should not be considered for an early resurgery. Second, the approach utilized should be chosen judiciously and no attempt should be made to perform a total resection if a well defined tumor-neuraxial plane is not available. In the light of the evidence provided above, observation or radiosurgery may be highly desirable options in the case of symptomatic recurrence of these lesions.
CG is a rare and presumably benign entity but with a controversial management. A minimally invasive surgery in the management of this tumor may be the optimum operative strategy. In particular, the subfrontal, supraorbital approach may be considered optimal, as it has a low complication rate and provides an adequate access to the lesion. In the cases of symptomatic recurrence, radiosurgery may be preferred over repeated intervention, considering the better results obtained in the literature and the low morbidity associated with this treatment. Nevertheless, due to the low incidence of CG, it would be necessary to collect a larger number of cases and to conduct a systematic analysis to reach more definitive conclusions.
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Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]