Fig. 47.1
CT scan of a clival chordoma (a) Axial slice showing a hypodense mass of the posterior aspect of the clivus (dotted line) contacting the brainstem (arrows) (b) Axial slice on bone windows demonstrating a lytic lesion eroding the superior aspect of the clivus and posterior clinoid processes (arrows) (c) Sagittal slice on bone windows demonstrating a lytic lesion eroding the posterior cortex of the sphenoid bone (arrows)
Fig. 47.2
MRI of a clival chordoma (a) Axial T1 post-contrast. Large hypointense, heterogenous mass (dotted line) of the posterior aspect of the clivus displacing the brainstem (arrows). Contrast enhancement is minimal and heterogenous. (b) T2 axial image showing a multilobular mass, hyperintense on T2 extending into the prepontine region and invading the two posterior clinoid processes. Hypointense intratumoural septations are seen (arrows) (c) T2 sagittal image. The chordoma is visible as hyperintense on T2, extending from the sella turcica to C5. Hypointense intratumoural septations are well seen (arrows)
Impairment of cranial nerve function is the principal presenting feature of chordomas of the cranial base, occurring in approximately 60 % of cases [43, 46]. The sixth nerve is most frequently involved (55–72 % of cases) [10]. Headaches occur in less than 40 % of cases [10, 46], occurring as part of an intracranial hypertensive syndrome (ICH) in 28 % of cases [46]. According to the same authors, long tract signs with a pyramidal syndrome occurs in 36 % of cases.
Children less than 5 years of age present more frequently with intracranial hypertension (72 %) or with long tract signs (43 %) than older children who present with diplopia or isolated headaches (55 and 42 %, respectively) [46, 51, 55].
Nolte was the first to describe four types of clival tumour extension (superior, inferior, anterior, posterior). The inferior extension, according to him, was more frequently found in children less than 5 years of age, perhaps explaining the frequent involvement of the long tracts and lower cranial nerves and the presence of torticollis [55].
47.2.4.2 Sacrococcygeal Chordomas
These present with the rapid appearance of an eventually ulcerated subcutaneous mass [56–58] occasionally massive within the presacral space. Perineal pain is often present and may be associated with radicular pain [58, 59] or cauda equina syndrome. Bladder and bowel dysfunction is common through compression and/or invasion of the nerves of the cauda equina or by direct compression of the urinary tract and colon by the presacral mass [56, 60].
47.2.4.3 Vertebral Column Chordomas (Figs. 47.3 and 47.4)
Fig. 47.3
Chordoma of the cervicothoracic junction with anterior extension (arrows) diagnosed due to respiratory difficulties (stridor)
Fig. 47.4
Cervical chordoma with posterior extension into the spinal canal (arrows) presenting with neurological involvement (right upper limb paresis, C5–7 radiculopathy)
The predominant symptoms depend on the orientation and development of the tumour. In the majority of cases, posterior enlargement of the tumour causes compression of the spinal cord or cauda equina [27, 41, 49, 61–63]. Anterior progression can present with respiratory dysfunction and/or dysphagia in those tumours of the cervical and thoracic regions [64]. In general, pain is common, often insidious in onset and becoming progressively more severe. The cause is mixed: displacement of soft tissues, bone destruction, nerve root compression, and vertebral instability [64]. Rigidity and/or spinal deformity have been similarly reported [27, 41, 65, 66].
47.2.5 Anatomical Localisation and Metastatic Dissemination
47.2.5.1 Anatomical Localisation
Skeletal Localisation (Fig. 47.5)
Fig. 47.5
Distribution of anatomical location of chordomas in the literature in adults and children from the literature and in our series
In the literature, childhood chordomas are clearly distinguished from their adult counterparts by their anatomical distribution. Adult chordomas are primarily found in the sacrococcygeal region [6, 9, 46, 55, 67], whereas in children, intracranial chordomas occur in the majority [7, 9, 27, 62, 68]. In our series, the majority of cases were situated at the level of the clivus and/or cervical spine.
Extraskeletal Localisation
Outside of these typical skeletal sites, ectopic extraskeletal chordomas have been described in children. We have not observed any in our series. They have been reported in the gluteal region [11], the paranasal sinuses [12], the ethmoid and maxillary sinuses [13], the temporal bone [14] and three cases of intradural lesions [15–17].
47.2.5.2 Metastatic Dissemination
The incidence of chordoma metastases is quite variable, from 10 to 48 % in adults [3, 6, 49, 53, 69] and from 8.6 to 58 % in children [9, 27, 28, 43]. It was 9.7 % in our series.
Metastatic spread seems to be the prerogative of the under 5-year-olds [10, 46, 70]. Tumours located in the sacrococcygeal region or of the spinal column seem to have a greater tendency to metastasize. In our review, the incidence in children was 55 % in sacrococcygeal chordomas with an average delay of 1.4 months, compared to 13.2 % for intracranial chordomas with an average delay of 4.5 months (Table 47.1).
Table 47.1
Incidence and delay to metastases in chordomas of children in the literature
Site | M+ | M− | UKN | M+ at diagnosis | M+ secondary | Avg. delay in months (med; min-max) |
|---|---|---|---|---|---|---|
Intracranial (n = 194) | 22 (13.2 %) | 145 (86.8 %) | 27 | 5 (3 %) | 6 (3.6 %) | 4.5 (1; 0–18) |
Sacrococcygeal (n = 22) | 11 (55 %) | 9 (45 %) | 2 | 5 (25 %) | 3 (15 %) | 1.4 (0; 0–6) |
Spinal column (n = 34) | 10 (41.7 %) | 14 (58.3 %) | 10 | 1 (4.2 %) | 3 (12.5 %) | 3.3 (2; 0–9) |
Metastatic dissemination primarily occurs via the blood circulation, particularly via the dural venous sinuses for clival chordomas [71], and the presacral veins for sacrococcygeal chordomas. Dissemination via the cerebrospinal fluid has also been reported, either via the subarachnoid spaces [70, 72] or through ventricular shunting [17]. There is also the risk of metastatic tumour deposition through the surgical route [73]. In our series, we reported one case of chordoma arising at the site of abdominal fat graft harvest, 10 months after the initial surgery.
The principal site of metastases is the lungs [9, 10, 17, 27, 40, 72, 74–76], followed by the bone [70, 76], lymph nodes (cervical, inguinal, subclavicular) [9, 27, 71, 76], skin [70, 77], liver [43, 70, 77] and anecdotally the brain and spinal cord [77], meninges [70, 72], heart [77, 78], pleural cavity [9], kidneys [77] and suprarenal glands [27, 46]. It is not uncommon for metastases to be present at diagnosis in contrast to that observed in adults. In our review of the literature, 25 % of patients with sacrococcygeal chordomas had metastases at diagnosis compared with 3 % of those with intracranial chordomas and 4.2 % of those with chordomas of the spinal column (Table 47.2). There appears to be a link between the incidence of metastases and local recurrence [43, 53]. In our series, metastases often occurred late in the illness (from 24 to 67 months) and each time was in the context of local recurrence.
Table 47.2
Progression-free survival and overall survival related to the length of follow-up in the major paediatric series and those of Necker-Lariboisière
Series | Number of patients | Av. follow-up in months (min-max) | Progression-free survival (%) | Overall survival (%) |
|---|---|---|---|---|
Benk et al. [43] | 18 | 72 (19–120) | 63 (5 years) | 68 (5 years) |
Borba et al. [10] | 79 (review) | 39 (1–300) | – | 56,8 |
Hoch et al. [44] | 73 | 90 (12–252) | – | 81 |
Ridenour et al. [28] | 35 | 129 (1–501) | – | 63 |
Necker-Lariboisière | 31 | 78 (0.3–239) | 54,3 (15 years) | 63 |
47.2.6 Management
Management of chordomas is multidisciplinary and relies on a collaboration between neurosurgeons, radiotherapists, radiologists, oncologists and sometimes ENT surgeons. Due to the poor outcome of the disease, management must be aggressive in order to limit the risk of local recurrence and metastatic dissemination. The advent of MRI, the advances in neurosurgery (endoscopy) and the contribution of proton therapy have allowed considerable prolongation of life for these patients. Today, treatment relies on as complete a surgical resection as possible followed by adjuvant radiotherapy by proton therapy. Standard chemotherapy has no role even if certain authors have utilised chemotherapy with occasionally encouraging results.
47.2.6.1 Surgery
Surgery is the essential step in the treatment of chordomas. The objectives are twofold: (1) maximal reduction in tumour volume with obtaining a macroscopically complete excision and (2) removal of any possible tumour residual away from the brainstem to maximise radiotherapy dose.
As in adults, all authors agree that the largest surgical resection possible must be achieved at the initial surgery [6, 7, 43, 79–82]. This attitude is commonly accepted, even if the paediatric series in the literature are too little to allow a real statistical analysis.
Ridenour observed a better survival following a complete excision versus an incomplete excision in 35 children, without achieving statistical significance [28]. We observed a similar result in our series, with a greater overall survival in patients with a complete excision before radiotherapy compared to those whose excision was incomplete.
The location of these tumours and the complexity of their extension allow a complete resection in the minority of cases [2, 83] due to the proximity to neural structures (cranial nerves, brainstem, sacral nerves) or vascular structures. Modern imaging techniques, neuronavigation, microsurgery and endoscopy have allowed surgeons to be more aggressive and to obtain better surgical excisions than in the past. However, the rate of complete surgical excision remains low in the major paediatric series published and varies between 0 and 36.4 %; it was 19.4 % in our series. These rates of clearance are less than those seen in other tumours of the cranial base in children (posterior fossa ependymoma, craniopharyngioma) [84, 85]. This is due to the fact that chordomas (1) are multilobulated tumours, often insinuated between nerves and arteries to which they adhere, (2) have osseous invasion and are located within the spine and cranial base whereby macroscopic clearance would cause significant mutilation and (3) often have an intradural component (50 % in our series) and sometimes insinuated within the dural layers.
Maximal tumour resection often requires many surgical attempts [86], in utilising different surgical routes in one or more procedures. In our series, 82 procedures were performed in 31 patients (on average 2.6 per patient). Complete excision was able to be achieved in only six patients (after one to three surgeries per patient).
The majority of routes to the cranial base currently used in adults may be applied to children with little modification and are well tolerated [87]: suboccipital [7, 61], retrosigmoid [16], infratentorial far-lateral and anterolateral [82], infra-temporal [55, 70, 88], transoral [43, 89–91] and transsphenoidal [7, 43, 92] routes. For spinal chordomas, the route can be posterior (laminectomy) [43], anterior (thoracotomy, retroperitoneal) or anterolateral [64], or a combination of these [63, 66].
In our series, the two routes used more frequently were the suboccipital retrosigmoid and anterolateral routes in 20.7 and 19.5 % of cases, respectively. When the tumors is originated from the clivus with an anterior extension into the sphenoid bone (body, sinus, sella turcica) and/or retropharyngeal, the classical routes employed have been transsphenoidal and transoral. This latter route was abandoned by numerous teams in favour of endonasal endoscopy [93, 94, 109], which is utilised to approach the craniocervical junction [110].
Orthopaedic management is rarely reported in the paediatric literature; in 34 cases of vertebral column chordomas, spinal fixation has only been reported in 3 cases [63, 64, 66, 68, 95]. In our series, the spine was involved in 22 children in whom 11 required fusion. Nine patients required temporary bracing.
Apart from tumoural reduction, the other objective of surgery is to remove as far as possible the tumour residual from functional anatomical tissues (spinal cord, brainstem, large vessels, internal auditory meatus, optic pathways and hypophysis) in order to deliver the maximal radiotherapy dose whilst minimising secondary effects.
47.2.6.2 Radiotherapy
Radiotherapy is an integral part of the treatment of chordomas, even if few paediatric series have truly evaluated the effectiveness of this treatment in this population.
Conventional Radiotherapy
Despite the fact that chordomas have been considered as relatively radioresistant tumours, the utilisation of high doses of conventional radiotherapy has provided a certain degree of tumoural control, and early on, the majority of authors have recommended adjuvant radiotherapy [1, 65, 96, 97].
Apart from isolated cases reported in the literature, only the series of Wold has provided long-term results of conventional adjuvant radiotherapy and surgical excision in an exclusively paediatric population [7]. In this series, Wold reported a group of 12 patients, with an average age of 13.6 years, presenting with intracranial chordomas (clival or of the sella region). All the patients had been treated by surgery primarily, radical (n = 4) or partial (n = 2) excision and unknown in 2; conventional adjuvant radiotherapy was given in 10 (5,115 rads on average, unknown in 4). The average follow-up was 67 months (1–252 months). During the follow-up period, two patients died from tumour progression after 26 and 44 months and two others due to unrelated caused (pneumonia in one and cause unknown in another). Survival rates in this series were thus close to 75 % at 5 years.
On another level, the interest in the association between surgery and radiotherapy in the paediatric population seems confirmed by Borba who in his review of the literature on intracranial chordomas confirmed that surgical excision, whether complete or incomplete, followed by radiotherapy (type not precise), offered a better outcome than surgical excision alone (p = 0.004) [10].
Proton Therapy
Radiotherapy in growing children has, however, its limits and can give rise to numerous complications [98]. In this context, proton therapy has become little by little the radiotherapy modality of choice in this condition [99, 100] in reducing by a factor of 2–3 the dose delivered to neighbouring structures (encephalon, hypophysis, cochlear…) [101]. In the series published by Hoch, 73 children had been treated for cranial base chordomas by surgical excision followed by proton therapy [44]. The average age at diagnosis was 9.7 years (1–18 years). The overall survival rate was 81 % with an average follow-up of 7.25 years (1–21 years). The authors considered the prognosis to be better than in adults where it ranged from 23 to 66 % in various series [102–104]. In the series of Benk, 18 cranial base and cervical chordomas were treated by incomplete surgery followed by fractionated radiotherapy as a mixture of photons and protons, to doses of between 55.8 and 75.6 CGE (median 69 CGE) [43]. The overall rate of survival progression-free survival at 5 years was 68 and 63 %. The authors considered the morbidity of the technique to be acceptable; two patients developed growth hormone deficiency requiring replacement, one patient developed an asymptomatic necrosis of the temporal lobe at last follow-up and three patients developed unilateral hearing loss.
In our series, all the patients were irradiated except two (one death in the immediate postoperative period, one tumour with rapid progression motivated chemotherapy at the outset). Routine access to proton therapy in our service commenced at the beginning of 2000: all the patients irradiated by photons alone were before 2001; thus, the majority irradiated by protons (alone or in combination with photons) were from 2000. Our series illustrates one of the interesting aspect of proton therapy, the ability to irradiate in higher doses without affecting surrounding healthy tissues in the majority: the average dose used was 55 Gy Eco in patients irradiated with photons alone, compared with 72 Gy Eco in patients irradiated with protons alone.
Of note in our series, 14 patients had tumoral progression. Six out of the seven children who died had been irradiated prior to progression, whilst six of seven survivors had been irradiated after progression. In cases of progression following radiotherapy, one can contemplate focal irradiation (Gamma knife, Cyberknife, Novalis).
47.2.6.3 Chemotherapy
Similar to adults, utilisation of chemotherapy in the management of paediatric chordomas is anecdotal with only 20 or so cases reported in the literature [7, 27, 43, 71, 77, 105–108]. In our series, only four patients had been treated by chemotherapy with disappointing results, all having died in the month following treatment.
Some authors consider that chemotherapy used for sarcomas can also be used in undifferentiated chordomas [77, 109]. The agent most commonly used is ifosfamide, frequently in association with étoposide [71, 105] or doxorubicin [105, 108]. In more recent years, Gleevec® (imatinib mesylate), a specific inhibitor of tyrosine kinase receptors (notably PDGFRα, PDGFRβ and KIT), has been used in adults with encouraging results [109]. Whatever the agent used, the indication for chemotherapy differs among authors, but is commonly the last option when all standard treatments (surgery and radiotherapy) are not possible or have failed.
Some very young children have been treated primarily with chemotherapy if the tumour has been considered inoperable or has already metastasised. Unfortunately, all these children died over some weeks to months [27, 71, 106, 108]. Lountzis has reported the only case of disease control with chemotherapy. This was in a 20-month-old child who presented with a clival chordoma extending to C1 with multiple metastases (cutaneous, cerebral, spinal cord, pulmonary, cardiac, hepatic and renal), treated by chemotherapy with cisplatin, doxorubicin, VP-16, vincristine and ifosfamide over 9 months with stability of the tumour. Due to the toxicity of the cumulated effects of the drugs used, second-line treatment with oral VP-16 was used for 24 months resulting in complete remission at 30 months of follow-up [77].
In other reports, chemotherapy has been proposed in cases of progression or recurrence of tumours previously treated with a standard protocol [7, 27, 43, 107]. This treatment seemed to have a benefit in only a small number of cases.
In our series, chemotherapy was not successful in disease control in any of the four children. None of our patients received ifosfamide-etoposide or ifosfamide-doxorubicin.
Based on recent studies in molecular biology, the tendency has become to use targeted therapies. Only adult series are available. Gleevec® (imatinib) has been utilised in a series of adult patients and infrequently in children (one child in our series). This tyrosine kinase inhibitor is specific for PDGFRα, PDGFRβ and KIT which are overexpressed on the surface of chordoma cells [109]; symptomatic and radiological improvement has been observed in adults treated with Gleevec® [109]. Inhibitors of the mTOR pathway (sirolimus) have also been used in cases of resistant chordomas [111]. A partial clinical response has been shown in a patient with metastatic chordoma of the sacrum treated with cetuximab/gefitinib, inhibitors of EGFR [112]. These observations need to be confirmed through large cohort studies with sufficient follow-up. With the exception of Gleevec®, these different agents have not been the subject of paediatric studies.
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