Introduction

Chordoma is a rare neoplasm that arises from embryonic notochordal remnants along the axial skeleton at developmentally active sites such as the ends of the neuraxis (i.e., clivus, sacrum) and the vertebral bodies. They comprise less than 1 % of CNS tumors and 1–4 % of all bone malignancies. Its peak incidence is between 50 and 60 years of age, and it rarely affects children and adolescents (<5 % of all chordomas) [18]. Even though histologically regarded as a low-grade neoplasm, chordomas are locally aggressive and highly recurrent [1, 6, 7]. This fact places them among the clinically devastating and therapeutically challenging tumors. Intracranial or skull base chordomas account for nearly 30 % of all chordomas and present at relatively earlier ages [23]. Their management is problematic for clinicians. Pediatric cases are quite rare and only small case series exist in the literature, thus standard management guidelines are lacking. In this paper, we present our center’s experience over six pediatric clival chordomas with a particular emphasis on predictors of prognosis, treatment options, and their changes in years in conjunction with clinical outcomes.

Materials and methods

This retrospective study includes six pediatric patients with pathological evidence of clival chordoma. These cases were identified over a period of 15 years in a tertiary care institute, which is a reference center in the region. All patients underwent both pre- and post-operative radiological evaluation by computerized tomography (CT) and magnetic resonance (MR). Surgery was the choice of treatment at initial presentation as well as at recurrence. Parental consent was obtained for each patient prior to surgical intervention. The type of surgical approaches included anterior (endoscopic endonasal transsphenoidal (EETS) and microscopic transoral (MTO) approaches) and posterior approaches (retrosigmoid (RS) and paramedian suboccipital (SO)). The extents of resections were classified into four levels based on amount of tumor removal; biopsy (10 % or less), partial (10–90 %), subtotal (more than 90 %), and near-total removal (no tumor on postoperative MRI). A tissue diagnosis was obtained in each of the cases in accordance with World Health Organization (WHO) classification criteria for chordomas (chordoma NOS, chondroid chordoma, and dedifferentiated chordoma).

Results

There were two boys and four girls with a mean age of 10.6 years (range, 4–16 years). Cranial nerve dysfunction, mostly of lower cranial nerves, was the major presenting symptom (66.6 %), followed by diplopia and headache. One patient had obstructive sleep apnea. All patients were operated and a total of 15 surgeries were performed (mean, 2.5). Tumor recurrence was observed in four patients (67 %). Two-year and 5-year progression-free survivals (PFS) were 67 and 33 %, respectively. There was no death due to surgery or during the follow-up period (6.9 years: 1–14 years) (Table 1). Detailed clinical histories of the cases are given below.

Table 1 Demographic features and tumoral characteristics of our cases
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Radiological evaluation

For pre- and post-operative evaluation, CT and MR imaging were obtained in all patients. The images unequivocally demonstrated destructive bony lesions with post-gadolinium enhancements. The lesions were located in upper (two cases), middle (two), and inferior (two) clival regions. There were generally multi-level involvements; the patients with upper and mid-clival involvements had a more favorable outcome both at intraoperative (with respect to extent of tumor resection) and postoperative period.

Histological evaluation

Two experienced pathologists performed histopathological evaluation. Microscopically, the specimens were composed of cellular organizations forming cord and lobular structures. Mucoid tissues could be discriminated between relatively small cells with invisible nuclei. Occasional physaliphorous cells with vacuoles and obvious nuclei were also observed. In four patients with these characteristic features, chondroma, NOS was the diagnosis.

In one patient, the diagnosis was chondroid chordoma based on the microscopic appearance demonstrating a prominent lobulated pattern and cartilage formations. In another patient, dedifferentiated chordoma was diagnosed due to presence of a sarcomatous component in the histological specimen.

Illustrative cases

Case 1 (patient 4, Table 2)

Table 2 Characteristics for our series regarding age, gender, clinical presentation, and duration in addition to lesion localizations and histological features with management strategies and outcome of the patients
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A 15-year-old girl presented to the outpatient clinic with diplopia for 1-month duration. Her neurological examination was normal. Her MR scan showed a homogenous mass (2.1 × 3.4 × 2.7 cm) arising from dorsum sella and posterior basisphenoid that extended to prepontine cistern, compressing basilar artery and pons posteriorly, displaced and elevated pituitary gland anterior and superiorly and protruded to right sphenoid sinus Fig. 1a, b. The tumor was excised through neuronavigation-guided endoscopic endonasal transsphenoidal surgery. Her diplopia resolved postoperatively. The pathology showed a chordoma, NOS. Postoperative MR imaging confirmed total tumor resection Fig. 1c, d. No adjuvant treatment was given. Follow-up for 3.5 years was uneventful.

Fig. 1
figure 1

Case 1 (patient 4). Sagittal pre- (a) and post-contrast (b) T1-weighted (W) images show a mass of dorsum sella and basisphenoid compressing the basilar artery and brainstem and elevating the pituitary gland. Pathological examination showed chordoma, NOS. Transsphenoidal surgery was performed. Pre- (c) and post-contrast (d) T1W images show total resection of the mass. Please note the T1 hyperintensity of fat impaction in the surgical bed

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Case 2 (patient 5, Table 2)

A 9-year old boy who had been suffering from obstructive sleep apnea (OSA) and dysphagia for 3 years presented to our outpatient clinic with the progression of symptoms for the previous 2 months. On examination, he had torticollis, hypoglossal nerve palsy, and hyperactive deep tendon reflexes. Radiologic examination revealed a mass lesion located in the mid-to-inferior clival region extended to the right prepontine cistern. He underwent subtotal resection via right retrosigmoid approach. His symptoms had improved postoperatively. The pathology showed a chondroid chordoma with Ki67 index of 2–3 %. Fifteen months later, he presented with imbalance, vertigo, OSA, and the neurological examination showed nystagmus, right hemiparesis and lower cranial nerve palsies. Tumor progression was detected on MR imaging (Fig. 2a, b). He underwent a second operation with right retrosigmoid approach, which resulted in improvement of the symptoms (Fig. 2c, d). Two years later, tumor recurrence was encountered when he had presented with the progression of OSA symptoms, nystagmus, lower cranial nerve palsies, and right hemiparesis. Endoscopic endonasal transsphenoidal surgery achieved subtotal tumor resection. Postoperatively, he received 5600 cGy intensity-modulated radiation therapy (IMRT) followed by ifosfamide plus etoposide chemotherapy. While there was no significant effect with this chemotherapy, the addition of imatinib resulted in tumor regression, as demonstrated by a follow-up MR imaging 6 months later. He was alive with minimal symptoms, and using CPAP for obstructive sleep apnea syndrome (OSAS) at the last follow-up visit.

Fig. 2
figure 2

Case 2 (patient 5). Sagittal T1W (a) and axial T2W (b) images display a mid-to-inferior clivus mass, pathologically proved chondroid chordoma (with Ki67 index of 2–3 %) in a previous surgery with retrosigmoid approach. The mass is seen to compress the brainstem, most prominently at the medulla oblongata and cervicomedullary junction. Sagittal TW (c) and axial fluid-attenuated inversion recovery (FLAIR) (d) images display minimal midline residual tissue with a right petrous apex lesion (asterisk, d). Please note the marked decrease in the brainstem compression (arrow, c)

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Discussion

Chordomas, despite derived from embryonic remnants of notochord, are majorly tumors of elderly. The incidence in general population is less than one in a million [16, 32]. Among these, less than 5 % are children, making chordomas exceptional cases in pediatric population [18]. The overall incidence is approximately 0.1–0.7 % of all pediatric intracranial tumors [18, 26]. Moreover, by its nature, the chordomas can be observed through all spinal axis; sacrum to skull base. The site of involvement differs depending on the age groups; in spite of predominance of sacral involvement in elderly [17], the chordomas mostly affects the skull base in youngsters [23]. Even in a large series of chordomas in children, there were no single cases of sacral involvement, and the majority (70.9 %, 22/31 cases) were located in the intracranial compartment, followed by craniocervical junction and cervical spine [10]. In this report, particular attention was paid to the clinical significance of and management strategies for clival chordomas in the pediatric population, which are rare and yet challenging entities in clinical practice. Thus, the numbers should be interpreted accordingly in the remainder of this article.

The literature search revealed a slight female predominance (F\M: 1.3) with the peak age of 10 years for the intracranial chordomas [12]. However, there is a paucity of demographic data particularly for the clival involvement due to being discussed with other skull base chordomas [19, 32]. The clinical presentations for skull base chordomas were grouped into two with respect to age. Borba et al. [3] defined that younger than 5 years, the children commonly presented with signs of increased intracranial pressure and sixth-nerve palsy (72 % each), followed by quadriparesis and lower cranial nerve palsies (dysphagia or dysarthria in 43 %). On the other hand, the figures changed in those older than 5 years of age; sixth-nerve palsy and lower cranial nerve findings were more common (each 55 %). Headache (42 %) was only reported in the latter group. For clival chordomas in particular, diplopia, esotropia, and lower cranial nerve palsies were specified in the literature [8, 11]. In our series, the majority (66.6 %) of the patients presented due to signs of lower cranial nerve palsies. Our numbers of sixth-nerve palsies were comparatively low with respect to the literature.

The authors of this article realized that the patients presenting with diplopia (or without signs of lower cranial nerve palsies) had a more favorable outcome even without radiotherapy. We performed a literature review for such a trend. Although it is not particularly defined in the literature, Harada et al. [11] presented a girl complaining of bilateral abducens palsy, diplopia, and esotropia at the age of 14 years. The tumor could have been removed totally through transsphenoidal route with relief of the symptoms. On the other hand, Fink et al. [8] presented 10-year-old with a clival chordoma. The presentation was dominated by lower cranial nerve palsies. Only subtotal removal had been achieved by transoral transclival route. The patient needed further radiotherapy. Wold et al. [33] presented 12 pediatric patients; eight of these cases involved mid- and inferior- clivus. The series had four cases with pure sixth-nerve involvement; all patients had total removal of the tumor (in one case degree of removal was not specified) and favorable outcomes, accordingly. These results merit future studies for prognostic significance of lower cranial nerve involvement.

There are some literature findings advocating the importance of histological subtypes and degree of surgical removal with respect to prognosis [10]. Thorough histopathological examination is important to discriminate chordomas from other mesenchymal tumors [21], possessing different biological behavior and therapeutic approaches [20]. Moreover, chordomas can exhibit some atypical histological features that group it into some subtypes based on microscopic and immunohistochemical studies [31]. Some of these atypical features challenge the diagnosis for chondrosarcomas [4] or rarely epithelioid sarcoma [21]. Borba et al. [3] reviewed 79 cases in the literature and documented that 64.6 % of cases had classical chordoma (chordoma, NOS), followed by atypical (dedifferentiated) (22.4 %) and chondroid chordomas (23 %). The prognosis was also interrelated to the histological subtypes. Their review yielded 100 % mortality for “atypical” cases, on the contrary to those of 37.5 % and 23.1 % for chondroid and “classical” counterparts [3]. These figures are majorly supported by some other reports with slight differences in the percentages [10, 12, 24]. Hoch et al. [12] also reported unpromising mortality rates for dedifferentiated group (83 %). With respect to our series, we did not observe any difference pertaining to histological subtypes, also which may partly be affected by the limited number of patients. Similarly, Dhall et al. [7] reported relatively subtle prognostic significance regarding these subtypes compared to the literature. Indeed, regarding the outcomes in our series, the population is not large enough to make definitive conclusions for biological behavior of clival chordomas.

Surgery was advocated as the mainstay treatment for the clival chordomas [15]. The strategies should aim at maximal resection of the tumor with best neurologic status [2]. Previous literature reviews demonstrated successful radical resection in only 31 % of the cases, in addition to high rates of mortality in postoperative period (as much as 37 %) [3, 7].

The importance of surgical corridor increases parallel to prognostic significance of resection rates. The route can be determined based on tumor location and extension to surrounding structures. The approach may be either anterior or posterior. Anterior approaches include microscopic transoral, transsphenoidal, and transmaxillary approaches as well as endoscopic endonasal technique [31]. The posterior approach usually includes retrosigmoid or suboccipital approach. The strategy should aim at removing as much tumor as possible while preserving maximal neurological status. We do not advocate total tumor removal at the expense of functional neurological condition. If total removal is not feasible, subtotal resection should be performed and the patient should be referred to radiotherapy and\or chemotherapy. Our figures represent this philosophy; all of our cases were operated on with subtotal resection of the tumors. Indeed even in two patients, no adjuvant therapy was implemented. The overall outcome in our series is favorable despite recurrent surgeries in four of our patients. Our strategy was also supported by literature findings. Chordomas in small volumes were reportedly managed efficiently with radiotherapy [22].

Endoscopic approach in the management of clival chordomas is also worth discussing because even in experienced hands, ventral approaches provide a complete resection in 79 % of the cases, with most [1] averaging around 50 % [28]. Additionally, endoscopic technique was also advocated by Al-Mefty in an article about anterior clivectomy technique [1]. The authors, despite performing a microscopic approach, stated routine usage of the instrument as an adjunct to microscope for visualizing beyond anatomical curves. Thus, this relatively new instrument, the endoscope, has been popularized as the primary modality of surgery. They offer a direct route through sinuses to anterior clival region without extensive removal of osseous structures [9, 14]. Use of an endoscope in the pediatric population was addressed in a study by Rigante et al. [25]. They encouraged use of the endoscope in children based on results comparable to microsurgical approach and a less complicated postoperative period [25]. Fraser et al. [9] reported their experience with endoscope use in 49 patients. The rate of radical resection was 87 %. The authors recommended using this technique particularly for the clival tumors located in the midline without significant extension to carotid artery [9]. We have used the endoscope in four of our patients. The surgical approach was more satisfactory in those patients with upper-to-mid clival involvement. We conceived that implementing the endoscope as the primary modality is preferable for preserving anatomical structures and exploring the tumor extensively. In recurrent cases, on the other hand, the borders and planes are generally disrupted. We experienced the technique in two recurrent cases, previous surgeries intimidated us due to unpredictable adhesions between critical neurovascular structures. Thus, the extent of resection was limited.

Fraser et al. [9], despite their high rates of complete resection, favors postoperative radiotherapy for stabilizing residual tumors. Indeed, in three of our patients, the satisfying extent of resection and benign histological features (namely chordoma, NOS) encouraged us to follow-up without any adjuvant therapy (Table 2). However, contrary to those with pure sixth-nerve palsy, one patient (case 6) had an early recurrence at 6 months. Thus, our empirical experience deduced rather aggressive behavior of the tumors in patients with lower cranial nerve involvement. This can be explained by complex anatomical relations at inferior clival region rendering successful surgical removal at risk.

Considering the relatively low rates of complete resections, clival chordomas are generally irradiated by conventional radiotherapy, stereotactic radiosurgery (SRS), or proton-beam radiotherapy (PBRT) [30, 34]. The discrepancy between the tolerance dose for neural tissue (brainstem in particular) [5] and the effective dose of radiation for chordomas (60 to 70 gray) [8] complicates radiotherapy in these children [7, 29]. Use of SRS and PBRT was advocated in order to overcome radiation-induced neural injury [5, 13]. George et al. emphasized the positive contribution of PBRT to overall survival, in particularly patients with skull-base chordomas [10]. Moreover, addition of chemotherapy is yet to be studied in detail in the management of these tumors. The reports are based on anecdotal experiences [7, 27]. We experienced SRS and intensity modulated RT in four patients, in addition to ifosfamide (IFOS) and etoposide (ETOP) chemotherapy in one. In our country, there is no center equipped with PBRT. We could not experience this therapeutic modality in our cases. However, we still observed that functional survival could be achieved in most of the patients with subtotal removal of chordomas and adjuvant radiotherapy.

Our study has several limitations. The population is small in number and not homogenous with respect to management strategies over a relatively extended period (15 years). The experience and improvements in surgical equipments (neuronavigation and endoscope in particular) would have changed our initial access route in management of clival chordomas. Moreover, unavailability of PBRT in our country rendered implicating other radiotherapy modalities to our patients. With this respect, the results should be cautiously evaluated. Thus, outlining a widely applicable list of recommendations for management is a difficult task. Our empirical experience regarding better prognosis in patients with pure sixth-nerve palsy (in other words without lower cranial nerve involvement) needs further support in future studies.

As a conclusion, clival chordomas are challenging tumors in neurosurgical practice. A multidisciplinary approach is warranted in each patient. Today, the best management strategy seems to be surgical resection followed by radiotherapy. Chemotherapy should be considered in selective and preference basis. Sharing institutional experiences will provide future insights in prognosis of these rare tumors.