Chordomas and chondrosarcomas are divergent tumors, based on their immunohistologic features. They share some similarities with regards to anatomical location, clinical presentation, radiologic findings, and treatment options.¹ Their names may sound similar but are indicative of their different histologic origin. Chordomas originate from remnants of the primitive notochord (chord means string), whereas chondrosarcomas are cartilaginous neoplasms (chondros means cartilage).

Both are rare malignancies, and their incidence in the pediatric population is even less, compared with that in adults. In an analysis of chordoma patients,² the age-adjusted incidence rate was 0.08 per 100,000. It was age dependent, more common in males (1.7/1), and rare in patients younger than 40 years. The median age of diagnosis was 58.5 years. Chordomas represent 0.1 to 0.2% of all intracranial tumors³ and 1 to 4% of all primary bone tumors.⁴ Less than 5% of chordomas are diagnosed in the pediatric population.² They account for only 4.5 to 15.2% of intracranial tumors in children and adolescents.⁵ Traditionally, it was thought that the sacrum is the most common location, followed by the spheno-occipital region and the mobile spine. Larger series showed that the anatomical distribution among these three areas is almost equal,^2,​6 with the pediatric patients representing an exception. More than 60% of chordomas in children are found intracranially.⁷

Chondrosarcoma is the second most common primary malignancy of the bone after osteosarcoma.⁸ The highest incidence is in the fifth and sixth decades. It originates from cartilaginous tissue and represents 0.15% of all intracranial space-occupying lesions and 6% of all skull base tumors.⁹ Similarly to chordomas, chondrosarcomas are found rarely in children. In a single institute analysis of 109 patients,¹ in the age group of patients younger than 17 years, there were 11 cases of chordomas, 5 cases of chondroid chordomas, and no cases of chondrosarcoma.

30.2 Pathology

When Virchow first described the microscopic features of chordomas, back in 1857, he emphasized the unique intracellular bubble-like vacuoles that he named physaliphorous.⁴ It was later suggested and widely accepted that these tumors arise from undifferentiated notochordal remnants throughout the axial skeleton. Today, with regards to their histopathologic features, three groups are described¹⁰: (1) the classical or conventional type that appears to be the most common and where the typical physaliphorous cells within abundant myxoid matrix are found; (2) the chondroid type where along with the classical features, additional areas of chondrosarcoma-like cartilage are found; and (3) the dedifferentiated type with aggressive sarcomatous appearance and absence of myxoid matrix. The seminal study by Borba et al⁵ analyzed children and adolescents with cranial chordomas and showed that 64.6% had the classical type, 13.5% had the chondroid type, and 22.4% had the atypical dedifferentiated type. Each type resulted in a much different prognosis, with the classical one possessing the better and the atypical type the worse prognosis. More recent studies with pediatric patients revealed similar results.^11,​12 It is thus of paramount importance to establish a direct and accurate pathologic diagnosis before resection that would determine further management and prognosis. Very often, needle biopsies are performed with care to avoid tumor seeding.⁴ Definite histopathologic diagnosis can be impossible if the samples are not representative of the prominent type. Besides the microscopical features, several immunohistochemical stains are used for the differential diagnosis. The most universally used markers that are often positive for chordomas are the S100, cytokeratins, vimentin, and epithelial membrane antigen (EMA). Chordomas and chondrosarcomas share S100 reactivity, and epithelial markers such as cytokeratins and EMA are used to distinguish them. But these can be difficult to assess in small biopsies. Additionally, they can both be positive in classical and chondroid chordomas¹ ( ▶ Fig. 30.1). Today, the most specific immunohistochemical marker for chordomas is brachyury,^{13,​14,​15} a nuclear transcription factor with a key role in the formation of the posterior mesoderm and axial development. Cytokeratin staining together with brachyury expression offered 98% sensitivity and 100% specificity for chordoma detection.¹⁶ On the other hand, a study from Japan identified a brachyury-negative chordoma type that showed a better prognosis compared with the brachyury-positive counterpart.¹⁷ Additional markers were found to correlate with prognosis and showed differences between pediatric and adult patients. High MIB-1 labeling index, p53 expression, and INI1 loss were related to worse prognosis, and they were more frequent in pediatric patients.¹⁸ Another marker, very frequent in adult chordomas but present only in 50% of pediatric patients was E-cadherin.¹⁹ Low expression of this marker was related to more aggressive course and higher recurrence rates, features that are seen often in childhood chordomas.

The most frequent type of chondrosarcoma is the conventional or classic type. It accounts for more than 80% of the cases. The main feature is cells that produce hyaline or myxoid cartilage. Subdivisions are the low (I), intermediate (II), and high (III) grades, based on mitotic rates, cellularity, nuclear size, and chondroid matrix. Other types are the dedifferentiated, mesenchymal, and clear cell.²⁰ Intracranial chondrosarcomas are typically of the classic type and low to intermediate grades. Less frequent is the mesenchymal type that tends to be more aggressive, and accurate discrimination between these types is crucial. In a case report published in 2014, a fusion gene named HEY-NCOA2 was successfully utilized for the identification of an intraspinal mesenchymal chondrosarcoma in a 10-year-old girl.²¹ Chondrosarcomas can be primary or secondary from preexisting benign cartilaginous tumors, like osteochondromas. They are common in patients with Ollier’s disease, Maffucci’s syndrome, and Paget’s disease.

30.3 Clinical Presentation

A wide spectrum of clinical manifestations can be seen in a patient with chordoma. These depend on the patient’s age and the location of the lesion. Chordomas are regarded as slow-growing tumors and as such the initial signs and symptoms can be nonspecific and long lasting. Rarely do they give metastases to the lungs, bone, skin, and brain.⁴ At the time of the initial presentation, they are metastatic at 5% of the cases and in very advanced diseases, up to 40 to 65%. In children, metastases are found more often in patients less than 5 years of age.⁵

30.3.1 Clival–Spheno-occipital Tumors

This area is the most common location for chordomas in childhood. The growing tumor destroys the clivus and in advanced cases, the anterior parts of the upper cervical vertebrae. It expands anteriorly into the nasopharynx and posteriorly, displacing the brainstem. It can extend into the spinal canal, lateral to the neck triangles and further intracranially, with significant involvement of crucial neurovascular structures. For older children, the prominent symptoms are neck pain, headache, and diplopia. They can be present for many months or even years. Involvement of the lower cranial nerves presents with dysphagia, dysarthria, drooling, torticollis, and recurrent respiratory infections. Superior extension to the sellar and parasellar regions would produce visual and endocrine dysfunction, but this is rare for the pediatric patients. Very often the first referral is for ear, nose, and throat (ENT) consultation for possible tonsillectomy and adenoidectomy. Some children would present with epistaxis, snoring, and nasal congestion. An evident nasopharyngeal mass should prompt further investigations. Detailed clinical examination can reveal additional cranial nerve palsies, namely, III, VI, and less frequently VIII, which can manifest as deafness in advanced cases. Long tract signs and symptoms (quadriparesis, ataxia) are frequent sequelae with brainstem involvement. In younger children, signs and symptoms of increased intracranial pressure are common. Hydrocephalus may result from obstruction of the cerebrospinal fluid (CSF) pathways or from venous congestion. Failure to thrive, poor feeding, loss of developmental milestones, and regression of gross motor skills—especially head support and balance—are expected signs in toddlers with advanced disease. In a small percentage of children, other anomalies occurred, such as hemothorax, kyphosis, and cutaneous stigmata, in association with tuberous sclerosis and neurofibromatosis.⁵

30.3.2 Mobile Spine and Sacrococcygeal Tumors

Again, the slow-growing pattern of these tumors has insidious results. The first symptom is localized deep pain and in later stages, radiculopathies, depending on the involved spinal level. Advanced disease may result in paralysis. Cervical tumors that expand anteriorly can produce throat irritation, dysphonia, esophageal obstruction, and Horner’s syndrome.²² Depending on the spinal level, bowel and bladder functions can be irreversibly compromised. Sacral chordomas in young children are a true diagnostic challenge. Usually they develop lower than the S2 or S3 levels, and they expand anteriorly into the pelvis. Invasion into the pelvic organs is limited by the presacral fascia.²³ As a result, the tumor can reach large dimensions before it becomes symptomatic. Severe constipation may be the first manifestation. Digital rectal examination is paramount in the early diagnostic evaluation and can detect a solid, rigid, presacral mass. In babies or even infants, sacrococcygeal chordomas and chondrosarcomas can present as evident bulging lesions at the gluteal region.

30.4 Imaging

Plain radiographs are the first option for imaging of a child with dull neck pain or low back pain without any neurologic deficits. Accurate diagnosis of a chordoma or chondrosarcoma based only on plain X-rays is almost impossible, but some indirect findings may be revealed. An alteration of the normal craniocervical junction measurements or a subluxation is not hard to identify. Deviation of the trachea and effacement of the sellar configuration can be additional findings. A levoscoliosis of the mobile spine often has neurogenic origin. In the sacral region, an accurate evaluation of the osseous structures is more difficult. Today, any suspicion of neurologic deficit should necessitate further imaging, ideally with magnetic resonance imaging (MRI). Besides the tumor characteristics, MRI will be the tool for surgical planning, neuronavigation, and future imaging. Ischemic insults, myelopathy, and syringomyelic cavities are also assessed. If a postresection spinal fusion is planned, the surgeon should be aware that further follow-up imaging with MRI would be less accurate because of the hardware artifacts. Computed tomography (CT) is ideal for delineation of bony pathologies. Chordomas appear as lytic lesions. CT angiography provides information regarding the patency of important arteries and their relationship with the lesion. Preoperative digital subtractive angiography (DSA) similarly will depict the vascular structures and additionally will give the option of embolizing a feeding artery, aiming to a decreased blood loss during the main operation. Another option during the DSA is the balloon occlusion test, in case of a major vessel that is involved in the planned tumor resection.

30.5 Treatment

30.5.1 Surgical

The role of surgery is crucial in the management of childhood chordomas. Their limited response to chemotherapy and radiation necessitates an aggressive surgical resection with tumor-free margins and minimum postoperative morbidity. This is a highly optimistic target that is very difficult to achieve, given their limited accessibility and their proximity to important and sensitive neurovascular structures. The rarity of such tumors in the pediatric population doesn’t allow safe decision-making conclusions for the optimum treatment strategies. Most of the current evidence comes from small case series and case reports. The offered plan is usually tailored to each patient’s characteristics and the experience of the multidisciplinary treating team.

Sacrococcygeal and Mobile Spine Chordomas

A review from 2011 on pediatric sacrococcygeal chordomas revealed less than 25 cases.²³ A combination of surgery and radiotherapy was the most frequent option, but the results were very poor. Kayani et al²⁴ reviewed the surgical management of sacral chordomas, and they found that large tumor size (more that 5–10 cm diameter), dedifferentiation, and greater cephalad tumor extension were associated with increased risk of disease recurrence and reduced survival. The surgical options are based on data from adult patients and are adjusted to reach the demands of childhood. Extensive, single-staged operations with significant blood losses are not tolerated by the pediatric patient. Large bony resections may have untoward impact to the growing skeleton, and in cases of postresection fusions, the surgeon must keep in mind the expected end points of the developing spine. Sacrectomy with wide resection margins is the ideal surgical management from an oncologic standpoint. The tumor capsule should remain intact, to minimize cell spreading and local recurrences.⁴ The degree of surgical aggressiveness should be guided by multidisciplinary oncologic consensus, and all the expected risks and benefits must be clearly explained to the child and the family. In advanced cases, surgery should aim for pain control and reduction of the neoplastic tissue for the following chemo- and/or radiotherapy. Posterior approaches are indicated for tumors at the level and caudally to S3 vertebra. They have an increased risk for visceral damage. For lesions that extend cephalad to S3, a combined anterior–posterior approach is preferred.²⁴ There is a 50% chance of normal bladder and bowel control when the S₂ roots are preserved.⁴ If one S3 root is additionally preserved, the chance significantly increases. A case report from 2014 described a long-term outcome of sacral chondrosarcoma in an adult that was treated by total en block sacrectomy and reconstitution of the pelvic ring. The authors used intraoperative extracorporeal high-dose irradiation of the autologous tumor-bearing sacrum, which was replaced in its previous position.²⁵ For lesions that involve the mobile spine, the same principles apply. The target is radical resection with maximum preservation of function. Almost always a combined anterior and posterior approach is utilized.

Spheno-occipital Chordomas

In children, the majority of chordomas are found in the spheno-occipital region. Skull base tumors are rare in the pediatric population, and such lesions should be treated in centers with experience in the complexity of these patients. Adult skull base surgeons can contribute as members of the team that consists of pediatric neurosurgeons, ENT surgeons, plastic–maxillofacial surgeons, and experienced anesthetists. The selection of surgical approach should be guided by the location of the tumor and the experience of the operating team. The target must be the safest possible tumor resection—“first do no harm.” Gross or near total resections can be very difficult in inexperienced hands. Several technological advancements have increased the resection rates of skull base tumors in children. Endoscopy, neuronavigation, neuromonitoring, preoperative embolization, local flap repair techniques, and elegant spinal fusion options offer a wide surgical armamentarium.

A detailed preoperative CT and MRI scanning is the base for careful examination of tumor location in association with the surrounding structures. CT angiography is very useful for neuronavigation purposes, together with MRI scans.²⁶ This will guide the surgical approach. If necessary, the resection can be done in two or more stages. For example, in cases of combined anterior and posterior (or lateral) approaches, or if the procedure is expected to last more than 8 to 10 hours.²⁷ The pediatric patient is vulnerable to excessive blood loss. A preoperative digital subtractive angiography (DSA) may help minimize such losses with careful embolization of tumor feeding arteries.

The transoral approach offers a wide exposure anteriorly to the clivus and upper cervical region.²⁸ The soft palate is usually divided in the midline to allow access superiorly to the clivus. Careful tongue retraction leads down to the lower C2 body. For lower access, to C3/C4 level, splitting of the mandible and tongue is necessary. This approach should be avoided in cases of active oral infection, limited mouth opening to less than 25 mm, and if there is fixed-flexion deformity of the neck. For the last reason, if a posterior midline approach for craniocervical fusion is planned, the transoral approach must proceed. Several other approaches to the pediatric skull base are similar to the adult ones, namely, the subfrontal, pterional, orbitozygomatic, subtemporal, and the rest of the lateral, posterior, and far lateral variations. Some differences between children and adults are important. The pediatric anterior skull base is more shallow and the sinuses less mature, allowing an easier access to deep lesions.²⁹ In children, male cases are predominant, as opposed to adults where female cases are more usual.³⁰ A possible explanation for that is the higher meningioma rates in adults. Children have better tissue planes, especially in craniofacial cases, allowing better surgical dissections and total resection rates. Usually they are first attempts, contrary to redo operations in adults.

The endoscopic endonasal approaches (EEAs) are becoming widely acceptable in pediatric neurosurgery. Their safety and efficiency are proven in adults, and encouraging results have been reported in children.^{31,​32,​33} New endoscopes, neuronavigation, and increasing neurosurgeon experience allow aggressive resections with safety. Traditional challenges in pediatric skull base endoscopy such as small working spaces, smaller basicranium, and incomplete pneumatization of the sinuses are now less important issues.³¹ Advantages of the EEAs compared with classical skull base microsurgery in children are the minimal invasiveness, respect to the developing facial skeleton, protection of the teeth, less brain retraction, and decreased hospital stay.³⁴ There is also a report of decreased need for postoperative adjuvant radiotherapy when the EEA was utilized.³⁵ The complication rate in experienced centers is reasonably low. Cerebrospinal fluid leaks were present in 10.5% in a series,³¹ and the use of vascularized nasoseptal flap had a significant impact to minimize this rate. Some limitations of the EEA for midline tumors are extension of the lesion lateral to the optic nerves and below the reach of the nasopalatine line.²⁷ Further lateral or posterior extensions may require staged and combined approaches. The poorly pneumatized sinuses and the underdeveloped pediatric skull base may result in less available anatomical landmarks and difficult orientation.³¹ Precise neuronavigation and experience are useful to overcome these drawbacks.

30.5.2 Medical

Traditional systemic chemotherapy is of limited value in the treatment of pediatric chordomas. Some centers individualize the given regimen according to limited data and aiming for minimal side effects. It can be considered as an option in cases of newly diagnosed solitary lesion with rapid increase in size pre- and postoperatively. The other option is for metastatic disease, tailored to the patient’s profile and life expectance.³⁶ Aggressive chemotherapy may have some effect on differentiated chordomas. Similarly, the response to chemotherapy is associated with the chondrosarcoma’s histopathology type. Conventional and dedifferentiated types have minimal or moderate response, whereas mesenchymal chondrosarcomas showed more favorable disease control.³⁷

Intensive research is currently focused on chordomas’ molecular biology and targeting of several genes, proteins, and signaling pathways. One of the first attempts was against the platelet-derived growth factor receptors (PDGFRB and PDGFRA) and KIT receptors with tyrosine kinase inhibitors (TKIs).³⁸ A well-studied TKI is imatinib, but such evidence in pediatric chordomas is very limited. Another pathway involves the epidermal growth factor receptor (EGFR), and the relevant inhibitors are cetuximab, gefitinib, and erlotinib.³⁶ In 2012, Diaz et al used high-resolution whole-genome sequencing of 21 skull base chordomas to show deletion of chromosome 9p involving CDKN2A, CDKN2B, and MTAP, in addition to loss of tumor suppressor fragile histidine triad expression, findings that may have important implications for chordoma pathogenesis and therapy.³⁹

The rarity of chordomas in the general population, and especially in children, limits the establishment of new therapeutic models. In vitro research and future clinical trials are based on the development of novel cell lines (U-CH1, U-CH2, JHC7 for chordomas and U-CS2 for chondrosarcomas)⁴⁰ with new cell amplification techniques, such as xenografts⁴¹ and differentiation therapies.⁴² Several ongoing open trials study the potentials of EGFR, brachyury, and hypoxia on chordoma treatment, but they focus on adult groups.⁴³

30.5.3 Radiotherapy

Aggressive surgical resection followed by local radiotherapy in solitary chordoma is the present mainstay of treatment. The amount of radiation delivered to the target depends on the anatomical location. In the sacrococcygeal region, higher doses are better tolerated, compared with the clival or spinal area. In the past, conventional external beam radiation alone was suboptimal, with local disease control rates of 10 to 40% at 5 years, with doses of 40 to 60 Gy.³⁶ In general, doses of 80 Gy cause radiation-induced myelopathy, and 70 Gy is currently the standard dose for chordomas. Challenges with radiation treatment in adults are magnified in the pediatric population.⁴⁴ The severity of late effects depends on the age of the child, the amount of normal organ irradiated, and the dose delivered. Whereas in adults these effects can manifest within 2 to 4 years, in children they may occur 5 to 10 years after treatment or later. Intellectual and sociobehavioral deficits after brain irradiation and impaired facial development are common late effects in children.

High-dose protons and charged particles (carbon or helium ions) are known as hadrons, and they are able to deliver higher doses of radiation to the tumor with minimum deposits to the surrounding normal structures.³⁶ Proton radiation therapy for residual skull base chordomas and chondrosarcomas was very effective and showed 5-year local control rates of 92% for the latter and 76% for the former.⁴⁵ The cutoff residual tumor volume for significantly better control was 25 mL. In a study with pediatric chordomas and chondrosarcomas, fractionated spot-scanning proton therapy was given postoperatively and the actuarial 5-year local control rates were 81% for chordomas and 80% for chondrosarcomas.⁴⁶ Other options for the delivery of higher doses are the intensity-modulated radiation therapy (IMRT) and the stereotactic radiosurgery (SRS).³⁶ The latter was found to be very effective for the treatment of small chordoma residual, especially in young patients, and achieved a 5-year local control rate of 80%.⁴⁷

30.6 The Hospital of Sick Children Chordoma Series Demographics

From 1987 until 2013, nine patients were operated for chordomas at the Hospital for Sick Children. Six were girls and three were boys (33%). Their age distribution was from 4.5 years to 13 years (mean: 9.6 years). All the chordomas were located at the clivus and the upper cervical spine area. ▶ Table 30.1 summarizes their management and outcome.

Related posts:

Surgical Decision Making in Chordomas Molecular Imaging of Chordomas Radiation Treatment for Chordomas Frontobasal Approaches to Clival Chordomas The Extended Petrosal Middle Fossa Approach Chordomas: A Personal Perspective

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