Chordoma of the skull base

INTRODUCTION — 

Chordomas are rare primary bone tumors thought to arise from vestigial notochordal remnants along the cephalocaudal axis, from the clivus to the sacrum. Although usually slow growing, they are considered malignant tumors that are locally aggressive with high rates of recurrence [1]. Chordomas involving the base of the skull pose unique challenges and require a multidisciplinary approach to management.

Chordomas of the skull base are discussed here. Chordomas arising in the sacrum or elsewhere along the spinal cord are discussed separately. (See "Spinal cord tumors".)

SKULL BASE ANATOMY — 

The skull base is defined as the anatomic junction of the neural and facial viscerocranium (figure 1A-B). This area is critically important because it supports the brain and allows all the neurovascular structures to either enter or exit the skull. Because of the delicate nature of these critical structures and the unique challenges they pose, pathology involving the skull base is usually considered separately from pathology elsewhere in the skeleton.

Chordomas of the skull base usually arise midline within the clivus, formed by the sphenoid bone (one-third) and the occipital bone (two-thirds). The base of the skull can also be involved as an extension of tumors arising in the craniocervical junction [2-4]. Although considered primary bone tumors, chordomas tend to spread within the skull base venous plexus.

EPIDEMIOLOGY — 

Chordomas are rare tumors with an annual incidence of 0.2 to 1.2 per million people worldwide [5,6]. They represent 1 to 4 percent of all primary bone malignancies and 0.2 percent of intracranial neoplasms [1,2,7]. Skull base chordomas make up approximately one-third of all chordomas; the remaining are roughly equally distributed between the sacrum and the rest of the mobile spine.

RISK FACTORS — 

Most chordomas are sporadic, and risk factors are not well understood. Chordomas can affect patients of all ages, with a peak incidence between 40 and 60 years of age. Males and females are affected equally.

Familial chordoma — Rare families with susceptibility to chordoma have been described, some in association with germline duplication of the T-box transcription factor T (TBXT) gene [8,9]. Factors that may indicate a higher likelihood of a genetic predisposition include young age at diagnosis, skull base location, and multiple primary chordomas [8,9]. Patients with a family history of chordoma and those presenting at an early age (eg, <30 years) should undergo complete imaging of the neuraxis to evaluate for multiple tumors and be referred for genetic counseling and testing.

Chordoma in early childhood can be seen rarely in patients with tuberous sclerosis [10], which is caused by germline gain-of-function mutations in the tuberous sclerosis complex 1 (TSC1) or TSC2 gene. (See "Tuberous sclerosis complex: Genetics and pathogenesis" and "Tuberous sclerosis complex: Clinical features".)

PATHOLOGY AND GENETICS

Pathology — Chordomas are thought to originate from remnants of the notochord and can occur anywhere in the neuraxis where notochordal differentiation took place during embryogenesis. Expression of brachyury, a key transcription factor in notochord development, is a hallmark of chordoma evident on immunohistochemical staining for brachyury [11,12].

●Histopathology – Histopathologically, chordomas are divided into three types [4]:

•Conventional chordoma – Conventional chordomas are the most common. They are characterized by the absence of cartilaginous or other mesenchymal components. Chondroid chordoma is a subtype of conventional chordoma containing matrix that mimics hyaline cartilage.

•Dedifferentiated chordoma – Dedifferentiated chordomas are biphasic tumors composed of conventional chordoma cells expressing brachyury as well as cells resembling high-grade sarcoma that do not express brachyury.

•Poorly differentiated chordoma – Poorly differentiated chordomas are epithelioid and solid tumors with focal rhabdoid morphology. They are characterized by homozygous SMARCB1 deletions, which can be detected immunohistochemically by loss of SMARCB1 (INI1) expression. Most of these tumors occur in children and are located in the skull base.

●Gross and microscopic pathology – On gross examination, chordomas are gelatinous pink or gray masses with solid and cystic areas. Microscopically, they are composed of lobules that contain epithelioid cells arranged in cords or clusters and separated by fibrous strands in a mucinous matrix. The tumor cells have vesicular nuclei and abundant vacuolated, soap bubble-like cytoplasm (physaliphorous cells; physalis is the Greek word for bubble) that contains glycogen (periodic acid-Schiff [PAS] positive) or mucin (picture 1). Nuclear pleomorphism and mitoses are uncommon. Ultrastructurally, chordomas exhibit epithelial features with prominent desmosomes [1-3,7,13,14].

●Immunohistochemistry – Tumor cells in almost all chordomas are diffusely and strongly positive for cytokeratin. Staining for epithelial membrane antigen (EMA) is present in more than 80 percent of cases, although it is typically more focal and less strongly positive than other antigen stains [3,4,15,16]. Brachyury staining is characteristic of chordoma and is only lost in dedifferentiated or poorly differentiated chordomas. Brachyury positivity is often used to help distinguish chordoma from other cartilaginous tumors [3,4,17].

Other immunostains are variable depending upon the type of chordoma. In one study, all 16 classic chordomas stained for keratin, while only 32 percent of 25 chondroid chordomas did [17]. In the same study, 44 percent of the classic and 85 percent of the chondroid chordomas were positive for S-100 protein [17].

Distinguishing chordoma from other pathologies such as chondrosarcomas, mucinous adenocarcinomas, and myxopapillary ependymomas is significantly aided by immunohistochemistry [2-4,15-17] (table 1).

•Chondrosarcomas do not express cytokeratin, while S-100 protein expression is present in both chondrosarcomas and chordomas.

•Tumor cells in chondrosarcoma and myxopapillary ependymoma are negative for cytokeratin and EMA, unlike chordomas. In addition, they do not have desmosomes on ultrastructural examination.

•Only myxopapillary ependymoma is positive for glial fibrillary acidic protein (GFAP), while chordomas and chondrosarcomas are negative for this marker. In one series, immunoreactivity was present for vimentin and GFAP in all cases and for S-100 protein in 50 percent of myxopapillary ependymomas.

•The differentiation of adenocarcinoma from chordoma may be difficult because both neoplasms are cytokeratin and EMA positive. Although positivity for vimentin and S-100 protein supports the diagnosis of chordoma over adenocarcinoma, this finding should be interpreted with caution, as rare adenocarcinomas may be positive for S-100 protein.

Mounting evidence suggests that more benign pathologies, such as ecchordosis physaliphora (EP) and benign notochordal cell tumor, exist on a spectrum of disease along with chordoma [7,14,18]. Both EP and benign notochordal cell tumors can have significant overlap with chordoma on gross pathology as well as immunohistochemistry. In contrast to chordoma, they exhibit an absent or very low mitotic rate and generally lack lobular architecture, fibrous septa, necrosis, and nuclear atypia [7,14,18].

Molecular prognostication — Among histopathologic types, dedifferentiated and poorly differentiated chordomas are associated with worse prognosis. However, the spectrum of outcomes within conventional chordoma remains very wide [19,20].

Several genetic signatures as well as molecular biomarkers have been associated with prognosis in chordoma and may prove useful clinically if validated [21,22]. In particular, 1p36 deletion and homozygous 9p21 (cyclin dependent kinase inhibitor 2A [CDKN2A]) deletion detected by fluorescent in situ hybridization (FISH) are associated with increased risk of recurrence [19,20]. Based on the proportion of cells containing these deletions, clival tumors can be stratified into three risk groups [19]:

●Group A/low risk (1p36 deletion in <15 percent of cells and 9p21 deletion in <4 percent of cells) – mean progression-free survival (PFS) 110 months

●Group B/intermediate risk (all other combinations of 1p36 and 9p21 deletion percentages) – mean PFS 59 months

●Group C/high risk (1p36 deletion in >15 percent of cells and 9p21 deletion in >25 percent of cells) – mean PFS 16 months

Other evidence suggests that smaller asymptomatic tumors in younger patients may be associated with more favorable prognostic panels [19], suggesting a possible spectrum between EP, benign notochordal cell tumor, and chordoma [7,14,18].

CLINICAL PRESENTATION — 

The diagnosis of chordoma is often delayed unless a tumor is discovered incidentally because of imaging obtained for other reasons. Early symptoms are often vague and nonspecific.

Most symptomatic patients with chordoma of the skull base present with diplopia and headaches. The diplopia is usually associated with lateral gaze and is due to a partial or complete abducens (cranial nerve VI) palsy.

As clival chordomas grow, they usually compress the abducens nerve within Dorello's canal, which is a dural cistern created as cranial nerve VI pierces the clival dura on its way to the posterior compartment of the cavernous sinus. The canal is bound by the petrosal process of the sphenoid bone inferiorly and the robust petrosphenoidal ligament superiorly (Gruber's ligament). Invasion of this space amounts to significant pressure on the abducens nerve, which can also be intermittent [23].

Significant bony destruction can cause spine instability leading to headaches and neck pain, particularly with craniocervical junction tumors (image 1) [2,24]. With larger tumors, presenting symptoms may include swallowing difficulties or imbalance from brainstem compression, strong headaches, nausea, and vomiting from the development of obstructive hydrocephalus, hearing difficulties from involvement of the eustachian tube, or airway obstruction.

EVALUATION

Imaging — Magnetic resonance imaging (MRI) is the best technique to assess the soft tissue extent of tumor and assess the extent of the intradural invasion.

Because of the water content within the mucin of chordoma cells, these tumors are typically multilobulated and bright on T2-weighted images, which can aid in diagnosis. This increased T2 signal stands out against the low T2 signal intensity of the bone within the clivus (image 2). They have an intermediate to low signal intensity on T1-weighted images. Contrast enhancement is variable; if present, it is usually heterogeneous [7,25]. Contrast enhancement has been associated with a poorer prognosis [26].

On computed tomography (CT), chordomas are almost universally osteodestructive. Intratumoral calcifications are rare. Chordomas tend to spread within the skull base venous plexus. As such, caudal extension in the spinal canal often represents extension within the perispinal venous plexus rather than true hematogenous spread.

Differential diagnosis

●Chondrosarcoma – Chordomas are similar radiographically to chondrosarcomas (image 3), and distinguishing between the two in the skull base can be challenging. Some clues are the following [3,7,13,25]:

•Chondrosarcomas usually originate from the petroclival synchondrosis and are therefore eccentric lesions. Chordomas usually arise from the midline.

•Chordomas extending along the skull base venous plexus tend to insinuate around the carotid artery, whereas chondrosarcomas usually displace it anteriorly (although they can also eventually encircle the carotid).

•Chordomas are less likely to have intratumoral calcifications associated with them, while these are more common in chondrosarcoma.

●Ecchordosis physaliphora (EP) – EP, a benign notochordal remnant, is described in approximately 2 percent of autopsy specimens and can mimic clival chordoma radiographically [7,14,25]. EP usually appears as a small (<2 cm), well-circumscribed focus of T2 hyperintensity on the dorsal surface of the clivus in the midline. Unlike chordoma, EP is nonenhancing and rarely shows evidence of clival erosion on CT. A characteristic bony stalk or pedicle at the base of the mass is present in approximately two-thirds of cases and is a useful diagnostic clue. EP is a radiologic diagnosis that can be observed in most cases; lesions with atypical imaging findings should be followed over time to ensure stability. Benign notochordal cell tumor is another entity that spans the radiologic findings between chordoma and ecchordosis [7,14,25].

●Other skull base tumors – Other skull base tumors can usually be distinguished from chordoma based on location and imaging features (table 1). These include:

•Meningioma (image 4). These are usually homogeneously enhancing, are associated with hyperostosis, have a wide dural base, and are typically less T2 bright. (See "Epidemiology, pathology, clinical features, and diagnosis of meningioma".)

•Pituitary adenoma (image 5) (particularly prolactinomas, which tend to be more extensive/invasive), craniopharyngioma (image 6), and other sellar/suprasellar masses. (See "Causes, presentation, and evaluation of sellar masses" and "Craniopharyngioma".)

•Olfactory neuroblastoma (esthesioneuroblastoma). (See "Olfactory neuroblastoma (esthesioneuroblastoma)".)

•Nasopharyngeal or paranasal sinus cancer. (See "Epidemiology, etiology, and diagnosis of nasopharyngeal carcinoma" and "Paranasal sinus cancer".)

Diagnosis — The diagnosis of skull base chordoma can usually be made purely by imaging when evaluated by experienced radiologists, and a definitive tissue diagnosis is made at the time of primary resection.

Biopsy of a suspected chordoma is associated with some risk due to tumor seeding, if done from a lateral or stereotactic approach, and potential compromise of reconstructive options when performed endonasally. Therefore, patients with suspected chordoma should be referred to an appropriate tertiary care center whenever possible prior to biopsy so that a definitive treatment plan can be formulated [1,3,25,27].

Biopsy is primarily reserved for cases in which the diagnosis is in doubt, pediatric cases when a poorly differentiated chordoma is more likely, or when the tumor may be thought to be unresectable based on imaging.

Extent of disease evaluation — We typically obtain complete neuraxis imaging (MRI of cervical, thoracic, and lumbar spine) in patients with suspected or newly diagnosed chordoma of the skull base to exclude spinal drop lesions, consistent with guidelines from the National Comprehensive Cancer Network (NCCN) [28].

Although chordomas can be staged according to the tumor, node, metastasis (TNM) system for primary malignant tumors of bone (table 2), this has limited prognostic value in the skull base region. We do not routinely obtain body imaging (CT or positron emission tomography [PET]/CT) for systemic staging unless there is clinical suspicion for metastatic disease, although NCCN guidelines endorse CT chest/abdomen/pelvis with or without PET for staging and consideration of bone scan if CT is negative [28].

MANAGEMENT — 

Skull base chordomas are rare tumors, and there are no randomized trials to help define optimal management. All treatment recommendations are derived from retrospective series and expert consensus [29].

Surgery — Surgery is the mainstay of treatment for chordoma. In contrast with spinal chordomas, where an oncologic resection with negative margins is usually possible, skull base chordomas are more difficult to resect due to the intricate neurovascular anatomy of the base of the skull.

●Surgical goals – Maximal safe resection is recommended in all cases; when it can be safely achieved, the goal is to remove bone and dura beyond the obviously involved tissue (supratotal resection) [28,30]. Gross total resection has been repeatedly shown to be associated with better outcomes [5,29,31,32]. Given the importance of maximizing degree of resection and the complexity of these procedures, which require highly specialized multidisciplinary teams, surgery should be performed at experienced centers.

The first attempt at resecting the tumor is also usually the one that allows for the best surgical outcomes, as scar tissue and compromise of local reconstruction options can become problematic in subsequent resections. As such, it is important that the first attempt at resection is performed by experienced multidisciplinary teams [27,29]. The occasional en bloc gross total resection of small tumors is often curative. Intraoperative or immediate postoperative MRI is used to evaluate for residual tumor, and further resection is planned accordingly.

●Surgical approach – The optimal surgical approach depends largely on tumor location. Skull base chordomas are midline lesions with an epicenter in between the cranial nerves as they exit the brainstem. Therefore, a ventral surgical corridor with an endoscopic endonasal approach is most commonly used [3,33-35]. There are some data to suggest that mucosa-bearing surfaces are more resistant to seeding, which is a potential advantage of the endonasal approach [36].

Additional traditional open approaches are often required to maximize the resection, especially for extensive tumors and those involving the craniocervical junction; these can be performed in separate stages [3,29,35].

●Outcomes and risks – Many patients experience improvement or resolution of tumor-related symptoms after surgical resection, including diplopia and headache. The main risks of surgery are spinal instability and cranial neuropathies, either transient or permanent, particularly of the abducens nerves. Other common surgical complications include cerebrospinal fluid leak, infection, and seeding of the surgical path [1,3,13,23,36].

Adjuvant radiation therapy

Patient selection — Adjuvant radiation therapy with protons has been traditionally considered the standard of care for skull base chordoma [37]. However, the need to universally employ this strategy has been challenged for select patients who undergo gross total resection [19,20].

●Subtotal resection or dedifferentiated/poorly differentiated histopathology – For all patients with residual disease after maximal surgical resection and all patients with dedifferentiated or poorly differentiated histopathology, we suggest adjuvant radiation therapy with appropriately high doses for chordoma, which is considered a radioresistant tumor. Chordomas are malignant tumors with a high risk of recurrence, and radiation therapy aims to eradicate gross and microscopic residual disease that cannot be safely removed with surgery [29,38,39].

●Gross total resection of conventional chordoma – Select patients with gross total resection may have long-term survival with surgery alone, and there is variability in care for these patients regarding adjuvant radiation therapy.

Given the significant variability in biologic behavior within conventional chordoma, some groups follow personalized paradigms to inform the need for adjuvant radiation therapy in patients with gross total resection. One institutional treatment algorithm uses the percentages of 1p36 and homozygous 9p21 (CDKN2A) deletions to identify patients with complete resection who may be candidates for deferral of adjuvant radiation therapy [19,20]. (See 'Molecular prognostication' above.)

Adjuvant radiation therapy remains a reasonable strategy for patients who wish to maximize upfront treatment and are willing to accept the risks of radiation therapy, as well as when the surgeon feels there may be high risk of residual microscopic disease.

Dose and technique — Given the high doses required for chordoma (typically 70 Gy or higher), conventional radiation therapy becomes difficult to use [29,40]. Instead, high-dose focused radiation delivery techniques with particles (primarily protons) or photons (stereotactic radiosurgery [SRS], stereotactic radiation therapy [SRT], and intensity-modulated radiation therapy [IMRT]) allow for higher doses of radiation therapy to be delivered to the tumor while sparing surrounding structures.

The most extensive data on chordomas come from proton beam therapy, but there are no randomized trials comparing these different contemporary techniques, and the advantages of proton beam therapy are primarily theoretical and anecdotal.

Conventional two- or three-dimensional radiation therapy techniques using photons have a significant risk of damaging the brainstem and cranial nerves, and the lower doses historically used with these techniques have been associated with a high rate of local recurrence and treatment failure. The limitations of photon therapy in the treatment of chordomas are illustrated by a series of 48 patients (20 with skull base lesions), 44 of whom had macroscopic disease following surgery [41]. The local control rate with conventional photon radiation was only 27 percent, although 85 percent of patients achieved useful and prolonged palliation of pain. The median survival was 62 months.

Charged particle radiation therapy — Charged particle radiation therapy offers several theoretical advantages over conventional photon radiation therapy to minimize incidental radiation therapy to adjuvant normal structures. The Bragg peak associated with this form of radiation is particularly beneficial when attempting to deliver high doses of radiation to the clivus in close proximity to the brainstem while maintaining a safe lower dose to the brainstem and other surrounding normal tissues. (See "Radiation therapy techniques in cancer treatment", section on 'Particle therapy'.)

Proton beam radiation therapy is the most widely used charged ion technique. This approach appears to be more effective than earlier use of conventional photon radiation therapy with lower doses of radiation:

●Proton beam – Proton therapy for chordoma is the prototypical charged particle radiation therapy and typically involves a total radiation dose of 70 to 78 Gy(RBE) [relative biological effectiveness]. In systematic reviews of retrospective studies, local control is achieved in approximately 75 percent of patients with three to five years of follow-up [38,42-44].

●Carbon ion – Carbon ion is a relatively newer modality, and pooled results show both favorable efficacy and safety in skull base chordoma. Compared with protons, carbon ion radiation therapy has better RBE. However, there are no available good-quality comparative studies to show any further benefit of one modality versus the other [45].

Photon techniques — Advancements in photon technology have enabled more conformal treatments, that is, the ability to concentrate high doses in a desired and sometimes complex-shaped target and reduce collateral radiation doses elsewhere. With these advancements, the dosimetric superiority of charged particle therapies has markedly reduced. There are no randomized trials that compare contemporary, advanced-technology SRS, SRT, or IMRT with proton beam or older photon techniques. However, the feasibility to deliver high radiation doses with photons is promising.

●Experience with SRS has been reported in multiple retrospective series [46,47]. In a systematic review that included 33 studies and 713 patients with skull base chordoma treated with SRS, 55 percent of patients were free of progression at last follow-up, and the mean time to progression was 48 months [47]. One of the caveats is that the overall volume of disease treated is generally smaller for patients who have received SRS, and little toxicity data are available. That said, SRS may have a valid role for treating small volume localized disease.

●SRT can be used for lesions that are too large for single-fraction SRS. In one series including nine patients with skull base chordoma treated with SRT, eight out of nine patients were alive at five years, although the mean follow-up was only 28 months among the entire cohort of 20 patients with mixed anatomical tumor sites [48].

●Preliminary data demonstrate the feasibility of IMRT for chordoma. However, in one report that included 24 patients with skull base chordomas treated with IMRT, a third of patients progressed locally at a median of 1.5 years despite a median dose of 76 Gy (range 60 to 78 Gy) [49].

Adverse effects — Adverse effects resulting from radiation therapy for clival chordomas can include:

●Hypopituitarism (predominantly anterior gland dysfunction) [39,41,42,45]. (See "Delayed complications of cranial irradiation", section on 'Hypothalamus and pituitary gland'.)

●Radiation necrosis (particularly of the brainstem or temporal lobes) (image 7) [39,41,42,45,50]. (See "Delayed complications of cranial irradiation", section on 'Brain tissue necrosis'.)

●Secondary malignancies (sarcomas, high grade gliomas, meningiomas) [39,41,42,45]. (See "Delayed complications of cranial irradiation", section on 'Secondary tumor formation'.)

●Cognitive dysfunction [39,41,42,45]. (See "Delayed complications of cranial irradiation", section on 'Partial brain radiation'.)

Follow-up and monitoring — The frequency of clinical and imaging follow-up varies depending on the outcome of treatments, the presence of residual tumor, as well as the genetic profile and overall concern for recurrence/progression.

A typical approach for patients with no residual tumor and low concern for recurrence is to obtain clinical and imaging follow-up three months after surgery, again in six months, and then yearly. Patients with residual tumor after surgery who receive adjuvant radiation are typically followed more closely, but once disease stability is established, follow-up intervals are increased.

Recurrent disease — Recurrences are very common in chordoma, and the management of recurrent disease is quite complex and generally requires a multidisciplinary evaluation [51].

When the recurrent tumor is thought to be safely resectable, surgery is generally the first choice, particularly if the tumor was not previously irradiated. If the tumor is relatively inaccessible or unlikely to be completely resected, SRS is a good option when the tumor is small. For multifocal, diffuse, or larger lesions, charged particle radiotherapy may be a better option [51,52].

In chordoma recurrences, dedifferentiation or sarcomatous transformation occurs in 2 to 8 percent [53]. Even without frank dedifferentiation, tumors that recur after radiation therapy are generally associated with a more aggressive course and worse prognosis. Multifocal, unresectable lesions that were previously irradiated should be considered for a clinical trial or for an off-label targeted therapy. This is especially true if distant metastases are present [51,52]. (See 'Advanced disease' below.)

Advanced disease — There is no standard or proven medical therapy for chordoma. Systemic therapy is most often used either as part of a clinical trial or as an off-label use [54,55]. That said, these options should be considered early in cases of poorly differentiated or recurrent/refractory dedifferentiated chordoma, particularly when metastases are present. Conventionally, anthracycline- or gemcitabine-based regimens are used as in other types of advanced soft tissue sarcomas [30]. (See "Overview of the initial treatment of metastatic soft tissue sarcoma".)

Clinical trial information is available from the United States National Institutes of Health (clinicaltrials.gov). The Chordoma Foundation is an additional excellent resource for clinicians and patients and families.

A variety of molecular targets are therapeutically relevant in chordoma and are being investigated in phase I/II clinical trials, including checkpoint inhibitor therapies, enhancer of zeste homolog 2 (EZH2) inhibitors (eg, tazemetostat), tyrosine kinase inhibitors (eg, imatinib, lapatinib), cyclin-dependent kinase (CDK) inhibitors, and brachyury-targeting strategies [54,55].

Studies reporting the use of molecularly targeted agents in patients with advanced chordoma are discussed separately. (See "Spinal cord tumors", section on 'Chordomas'.)

PROGNOSIS — 

Chordomas are rare bone malignancies with a high risk of recurrence, and long-term survival is guarded in patients with recurrent disease [6,56]. In a population-based study utilizing the Surveillance, Epidemiology, and End Results (SEER) database that included 643 patients with skull base chordoma, 5-year and 10-year overall survival was 77 and 62 percent, respectively [56]. Older age and larger tumor size were associated with worse prognosis. In contrast with multiple other reports, gross total resection was not associated with improved survival compared with subtotal resection, although confidence in this result is limited by the challenges of accurately defining extent of resection in population-based studies [5,29,31,32]. Adjuvant radiation therapy was also not associated with improved overall survival [56].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bone sarcomas".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: External beam radiation therapy (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Chordomas are rare primary bone tumors. Approximately one-third of chordomas arise in the base of the skull, usually within the clivus. (See 'Epidemiology' above.)

Risk factors are not well understood. Rare families with germline duplication of the TBXT gene have susceptibility to multiple chordomas, often at an early age (<30 years). (See 'Risk factors' above.)

●Pathology – Chordomas are thought to arise from remnants of the notochord. They are generally slow growing but are considered malignant and have high rates of recurrence. Most chordomas are classified as conventional chordomas comprised of conventional chordoma cells expressing brachyury. Dedifferentiated and poorly differentiated chordomas have more sarcomatous or rhabdoid features. (See 'Pathology' above.)

●Clinical presentation – Most patients present with diplopia secondary to abducens palsy or headache and neck pain from bony destruction and instability. (See 'Clinical presentation' above.)

●Neuroimaging – On MRI, skull base chordomas are typically midline tumors within the clivus or craniocervical junction. They are heterogeneously bright on T2-weighted images and have intermediate to low signal intensity on T1-weighted images (image 2). Contrast enhancement is variable. Chordomas show evidence of bony destruction on CT and rarely have intratumoral calcifications. (See 'Imaging' above.)

●Diagnosis – The diagnosis of chordoma can usually be made through imaging. Biopsy risks tumor seeding along the track and can compromise reconstructive options. Therefore, patients with suspected chordoma of the skull base should be referred to a comprehensive center before biopsy. Tissue diagnosis is typically made at the time of definitive resection. (See 'Diagnosis' above.)

●Initial therapy

•Surgery – For patients with skull base chordoma, we recommend maximal surgical resection (Grade 1C). Gross total resection is the most important predictor of improved outcomes, and as many procedures as required should be considered to maximize the degree of resection. (See 'Surgery' above.)

•Radiation therapy – For most patients with chordoma, we suggest adjuvant radiation therapy (Grade 2C). The chance of long-term survival after local relapse is low, and although chordomas are radioresistant tumors, adjuvant radiation therapy with appropriately high doses appears to improve progression-free survival.

One potential exception is in patients with gross total resection of a conventional chordoma. At the author's institution, such patients are stratified by 1p36 and 9p21 deletion percentages, and those with low- or intermediate-risk profiles are considered for observation after gross total resection. Adjuvant radiation therapy is a reasonable alternative for patients who wish to maximize upfront therapy and are willing to accept the risks of radiation therapy, and when the surgeon feels there may be high risk of residual microscopic disease. (See 'Patient selection' above.)

Both charged particles and photons have a role in the treatment of skull base chordoma. (See 'Dose and technique' above.)

●Recurrent disease – Treatment of recurrent disease is complex and should be evaluated in a multidisciplinary fashion. For patients with a safely resectable recurrence, we suggest surgery as the first step (Grade 2C). Treatment of other patients typically involves radiation therapy individualized based on prior treatment history, tumor size, and location of recurrent disease. (See 'Recurrent disease' above.)

●Advanced disease – There is no standard systemic therapy for chordoma, and clinical trial participation is encouraged. Use of targeted drugs with regulatory approval for other indications should be considered early in cases of poorly differentiated or recurrent/refractory dedifferentiated chordoma, particularly if distant metastases are present. (See 'Advanced disease' above.)

ACKNOWLEDGMENTS — 

The UpToDate editorial staff acknowledges Derrick Lin, MD, and Carl Snyderman, MD, MBA, who contributed to earlier versions of this topic review.