Chordoma 

Updated: May 03, 2022
Author: Cheryl Ann Palmer, MD; Chief Editor: Brian H Kopell, MD 

Overview

Practice Essentials

A chordoma is a low-grade, slow-growing, but locally invasive and locally aggressive tumor. Chordomas belong to the sarcoma family of tumors. They arise from remnants of the notochord and occur in the midline along the spinal axis from the clivus to the sacrum, anterior to the spinal cord. The location distribution of chordomas is 50% sacral, 35% skull base, and 15% vertebral bodies of the mobile spine (most commonly, the C2 vertebra, followed by the lumbar then the thoracic spine). Overall 5-year survival is approximately 50%, and treatment consists of en bloc surgical resection followed by high-dose conformal radiation therapy (RT) such as proton beam radiation.[1]

Chordomas can be divided into 4 subtypes: conventional, poorly differentiated, dedifferentiated, and chondroid. Conventional (classic) chordomas are the most common variety and may show areas of dedifferentiation. Poorly differentiated chordomas are more common in young adult and pediatric patients, as are skull base chordomas, and show loss of the INI1 gene. Dedifferentiated chordomas typically are the fastest growing and most aggressive chordomas and can also have loss of INI1; they are more common among pediatric patients. Chondroid describes chordomas that are difficult to distinguish from chondrosarcoma on histology. Typically, chordomas express the brachyury gene, whereas chondrosarcomas do not express this gene.[1]

Surgical therapy is indicated for these tumors, as they continuously grow, albeit slowly, and erode bone and adjacent soft tissue, causing marked destruction of surrounding tissue. Optimal therapy typically involves complete surgical resection, which is often technically difficult because of the anatomic location, leading to a high rate of recurrence. Lesions have generally been resistant to radiation and chemotherapy; however, experimental studies involving targeted therapy and immunotherapy are under way.[2]

Different histologic subtypes of chordoma differ in their prognosis. To date, no recurrent genetic drivers have been identified for this disease. Brachyury seems to play a key role in the pathogenesis of chordoma, although the detailed mechanism remains to be elucidated. Surgical en bloc resection with negative margins is the only curative treatment for chordoma. High-dose irradiation, particularly with protons and carbon ions, is a therapeutic alternative in cases of inoperable tumor. Currently, no medical treatment has been approved for treatment of chordoma. Clinical trials exploring additional therapeutic modalities are ongoing.[3]

(An image depicting a chordoma is shown below.)

This pelvic CT scan shows a large presacral mass e This pelvic CT scan shows a large presacral mass eroding bone.

History of the Disease

In 1857, Virchow originally described chordomas when he named them ecchondrosis physaliphora, believing they were cartilaginous in origin. In 1895, Ribbert pierced a nucleus pulposus and found similar tumors. From this bit of evidence, he correctly surmised the notochordal origin of chordomas.

Ecchordosis physaliphora is a term that refers to small, well-circumscribed, gelatinous masses adherent to the brainstem. Although composed of notochordal remnants, ecchordosis physaliphora seldom, if ever, progresses into chordoma. Ecchordosis physaliphora is a reported finding in approximately 2% of autopsy examinations, whereas chordomas are quite rare.

Rare, benign intra-axial tumors of notochordal origin have been described as "intraosseous benign notochordal cell tumors."[4, 5] These are distinguished from ecchordosis physaliphora by their intraosseous location, and from chordoma by their well-demarcated radiographic appearance, bland histologic features, and lack of soft tissue extension.

Chordoma is a clinically and histologically unique malignant neoplasm, and numerous diagnostic considerations must be excluded to establish the correct diagnosis.[2]  Although a chordoma is usually a slow-growing tumor, it is locally aggressive and has a tendency to infiltrate into adjacent tissues and organs. Local recurrence results in tissue destruction and generally is the cause of death. Metastases are recognized but are uncommon.

Epidemiology

Chordoma is a rare tumor that occurs along the axial spine in children and in adults, with an incidence of approximately 350 cases per year in the United States[6]  and a reported annual worldwide incidence of 0.08 per 100,000 cases.[3]

Chordomas typically affect those in the 40- to 60-year age group but have been reported in children and in the very elderly. Most believe males are more commonly affected than females, at an approximately 2:1 ratio, with an annual incidence of 1:1,000,000 for new diagnoses. Chordomas account for approximately 20% of primary spinal tumors and only 3% of all bone tumors. The most common location is the sacrum/coccygeal region (50%), followed by the spheno-occipital region (35%) and the mobile spine (about 10-15%).[1]

Less than 5% of chordomas occur in children. In a population-based study comparing pediatric versus adult skull base chordoma, Xu and colleagues reviewed data from the National Cancer Database from 2004 to 2015 on patients 18 years of age and older versus those younger than 18 years. They found that pediatric patients were likely to have larger tumor size (41.4 ± 15.7 mm vs 34.1 ± 15.8 mm; P< 0.01) and were universally treated at academic facilities. They found no difference in overall survival.[7]

Etiology

Chordoma is a rare bone cancer of unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown.[8]

Chordomas are thought to arise from primitive notochordal remnants along the axial skeleton. During development, the notochord is surrounded by the developing vertebral column. In adults, remnants of the notochord are present as the nucleus pulposus of the intervertebral discs. Notochordal remnants that are extradural are most common in the sacrococcygeal region but can be found at any site along the length of the axial skeleton. The distribution of tumors matches the distribution of notochordal remnants.

Genes implicated in chordoma formation include the brachyury gene and the mechanistic target of rapamycin (mTOR) signaling pathway, as well as deficiency of the phosphatase tensin homolog (PTEN) gene, INI1, and platelet-derived growth factor receptor-beta (PDGFR-beta), although no definitive genetic marker has yet been identified. Few familial clusters of chordomas have been reported.[1]

A genetic basis has been described for some chordomas. However, most exhibit complex abnormal karyotypes, including whole or partial losses of chromosomes 3, 4, 10, and 13; gains in chromosome 7; and rearrangements of chromosome 1p.[9] All these have been implicated in the pathogenesis of chordoma. Also, microsatellite instability resulting from DNA mismatch repair deficiencies has been demonstrated; however, no chordoma-specific translocations have been identified.

 

Pathophysiology

Chordomas present as slow-growing, locally invasive tumors; distant metastases occur rarely and only late in the disease. Although they are considered indolent tumors, there is significant risk for multiple local recurrences.[1]

Grossly, chordomas are variable in size. They are soft, gelatinous, smooth, or lobulated and are gray-white in color on their outer surface. On cut section, the tumor is homogeneous in color and consistency. Occasionally, calcifications or hemorrhages are present. Chordomas appear to be encapsulated when in soft tissue, but not when located in bone.

Ongoing research into the molecular pathophysiology of chordoma has led to the discovery of several pathways that may serve as potential targets for molecular therapy, including a multitude of receptor tyrosine kinases (eg, platelet-derived growth factor receptor [PDGFR], epidermal growth factor receptor [EGFR]), downstream cascades (eg, phosphoinositide 3-kinase [PI3K]/protein kinase B [Akt]/mechanistic target of rapamycin [mTOR]), brachyury—a transcription factor expressed ubiquitously in chordoma but not in other tissues, and the fibroblast growth factor (FGF)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. Continued research and advances in the field may lead to improved outcomes for patients with this challenging disease.[10]

Presentation

Clinical presentation is entirely dependent on the location of the chordoma.[11]

Skull base and clival chordomas typically present with headaches and/or cranial nerve dysfunction, most often involving cranial nerve VI (abducens nerve), although the lower cranial nerves can also be affected.[1]  With intracranial tumors, the most common presenting symptoms are diplopia and headache. Neurologic signs also occur in over 50% of patients, primarily as cranial nerve palsies. Palsies of cranial nerve VI and the sensory branch of cranial nerve V are most common.

Uncommon clinical presentations of intracranial tumors include CSF rhinorrhea, nasal obstruction, nasal bleeding, and subarachnoid hemorrhage.[12]  Rarely, a clival chordoma will present with rhinorrhea due to a cerebrospinal fluid (CSF) leak.

Cervical chordomas typically present with nonspecific neck, shoulder, or arm pain. Cervical chordomas can invade cranially to cause lower cranial nerve dysfunction, as well as compression of the spinal cord or exiting nerves, resulting in myelopathy or radiculopathy, respectively.[1]  Patients with tumors located along cervical vertebrae present with hoarseness, dysphagia, and, occasionally, pharyngeal bleeding. Other rare or unique symptoms have been reported but are the exception.

Patients with tumors located along lower vertebrae may present with pain, bladder dysfunction, or lower extremity weakness. Thoracic and lumbar chordomas are seen with nonspecific localized pain and may be the cause of a pathologic fracture or of radiculopathy or myelopathy. Sacral chordomas share a similar presentation as thoracic and lumbar chordomas with localized pain and possible radiculopathy, as well as possible dysfunction of the bladder, bowel, or autonomic nervous system if the tumor involves the lumbosacral plexus.[1]

Chordomas often present late in the disease course and tend to encapsulate adjacent neurovascular anatomy, seed resection cavities, recur locally, and respond poorly to radiotherapy and conventional chemotherapy—all of which make them challenging to treat. Extent of surgical resection and adequacy of surgical margins are the most important prognostic factors; thus, patients with chordoma should be cared for by a highly experienced, multidisciplinary surgical team at a quaternary center.[10]  The time span from onset of symptoms to diagnosis averages 10 months.

Prognosis

Chordoma is a low-grade notochordal tumor of the skull base, mobile spine, and sacrum that behaves malignantly and confers a poor prognosis despite indolent growth patterns.[10]

This is a clinically and histologically unique malignant neoplasm, and numerous diagnostic considerations must be excluded to establish the correct diagnosis. Treatment options have largely been centered on surgical excision with marginal results; however, novel therapeutic options including targeted therapy and immunotherapy offer promise for improved outcomes.[2]

Identification of molecular factors that are associated with survival contributes to better prognostication of patients with chordoma. Given the rarity of chordoma, often only univariate analyses can be performed. Robust multivariate analyses are scarcer but provide independently significant prognostic factors. At 10-year follow-up, the average survival rate is 50%, although individual prognosis varies substantially.[13]

A study based on analysis of Surveillance, Epidemiology, and End Results (SEER) data found that (1) marital status was an independent prognostic indicator for adult patients with chordoma, (2) married status was conducive to patient survival, and (3) compared with married patients, widowed patients are at higher risk of death.[14]

Despite the low-grade status of chordomas, they have a high recurrence rate and involve significant mortality. Five-year survival is approximately 50% overall but is improved to 65% with complete resection with negative margins. Surgical resection with positive margins is associated with approximately 50% 5-year survival, and if the chordoma is inoperable, 5-year survival is approximately 40%.[1]

Due to high local recurrence of chordomas, most physicians recommend lifelong surveillance with magnetic resonance imaging (MRI) with and without gadolinium contrast. Metastatic chordoma should be on the differential if new lesions arise elsewhere in the body, as up to 20% of chordomas can metastasize.[1]

Researchers who completed a population-based multivariate analysis to evaluate prognostic factors for patients with chordoma reported that older age, greater tumor size, and distant metastasis were correlated with decreased survival, whereas surgical resection was correlated with increased survival. Patients receiving radiation therapy also showed decreased survival—likely an indication of the patients' advanced stage of disease, making them poor surgical candidates.[15]

Immunohistochemical analysis of brachyury expression revealed that for classical and chondroid chordomas, the disease course cannot be reliably determined using only morphologic criteria. Brachyury (T gene) was shown to play a central role in chordoma pathogenesis. Recurrence-free survival and total survival were compared between brachyury-overexpressing and non-expressing groups using Kaplan-Meier survival analysis. Study authors concluded that brachyury expression in tumor samples is not a sensitive indicator of prognosis for patients with chordoma.[16]

A review of chordoma stated that chordoma is a complex disease because of its rarity, biological heterogeneity, and peculiar clinical behavior. Despite progress, the outcome of this disease remains unsatisfactory, and identification of active systemic treatments remains an urgent, unmet medical need. Significant steps forward have enhanced our comprehension of chordoma complexity, with insights gained into the biology and morphology of this disease. New entities have been described, and potentially druggable molecular targets identified.[17]

 

Workup

Imaging Studies

Evaluation of chordoma revolves around imaging and biopsy.[1] No laboratory studies are required for evaluation of chordoma, except as needed for routine preoperative evaluation for patients scheduled to undergo surgical resection. Plain radiographs may be useful to demonstrate the extent of bone involvement. Plain film radiographs may show an ill-defined endosteal margin or a bulky mass in the soft tissue. These lesions may be lytic. In general, and especially in clival chordoma, erosion of bone, particularly the tip of the clivus, and a sclerotic bone reaction are seen radiographically. The mass appears as a destructive, well-demarcated lesion. Discovery of these features can better clarify the diagnosis of chordoma in the differential of bony lesions.

Computed tomography (CT) imaging is better for demonstrating the destructive lytic chordoma. Occasionally, the chordoma will have sclerosis at the margin. Chordomas are hypodense compared to bones on CT and may demonstrate irregular dystrophic calcification. Chordomas show moderate to significant enhancement on contrast CT imaging.[1]

Magnetic resonance imaging (MRI) best delineates the extent of a chordoma. Chordomas have lower signal intensity on T1-weighted imaging and may show foci of hyperintensity, which represent intratumoral hemorrhage. T1-weighted imaging with gadolinium contrast demonstrates heterogeneous contrast enhancement of the tumor with a honeycomb appearance. On T2-weighted imaging, chordomas tend to be hyperintense. Gradient-echo MRI can confirm intratumoral hemorrhage.[1]

Bone scans are sometimes obtained during the workup, and chordomas are known to have normal to decreased uptake.[1]

On MRI, the appearance of a chordoma is similar to its appearance on CT scan, with better resolution of the soft tissue component, resulting in better anatomic definition, as depicted in the image below. Chordomas are hyperintense on T2 images and hypointense on T1 images.

This pelvic CT scan shows a large presacral mass e This pelvic CT scan shows a large presacral mass eroding bone.

 

Diagnostic Procedures

Imaging of the clivus usually reveals features adequate for differentiating chordomas from other site-specific lesions. In the sacrum, radiographic features are more similar to those of other common bone tumors, and although they may be suggestive of a chordoma, they are not diagnostic.

Biopsies of chordomas are useful only when other bone lesions remain in the differential diagnosis after imaging studies are performed. In this instance, tissue diagnosis by biopsy can enable optimal planning for surgical resection of the tumor. Fine-needle aspiration (FNA), the preferred method for establishing the preoperative morphologic diagnosis of chordoma, has been reported to lower local recurrence rates when compared with open biopsy.[18] Diagnostic criteria for chordoma in FNA include the presence of physaliphorous cells with round nuclei, bland chromatin, and distinct cytoplasmic borders in a background of abundant myxoid ground substance.

Many times, a needle or open biopsy is performed to confirm the diagnosis of chordoma. Care must be taken when the biopsy is planned and performed, as the chordoma can seed along the biopsy tract. Thus the biopsy tract should be included in the future chordoma resection to decrease the risk of local recurrence.[1]

Histologic Findings

Chordomas are divided into conventional, poorly differentiated, dedifferentiated, and chondroid types.

Chordomas show notochordal differentiation and are characterized by nuclear expression of brachyury (TBXT). Chordomas are localized in the axial skeleton, where they occur from the clivus to the sacrococcygeal region. They are slow-growing, locally destructive tumors that often are not diagnosed until they have reached an advanced stage. Putative precursor lesions are benign notochordal cell lesions, which are microscopically small and intraosseous. Different histologic chordoma subtypes differ in their prognosis.[3]

Microscopically, conventional chordomas are composed of uniform cells with small oval or round eccentric nuclei and dense chromatin. Hallmark microscopic features of chordomas include numerous, variably sized vacuoles located in the tumor cell cytoplasm and physaliphorous cells, as depicted in the images below. Some tumor cells may have more solid or eosinophilic cytoplasm.

A light microscopic view of a hematoxylin and eosi A light microscopic view of a hematoxylin and eosin (H&E)–stained section of a chordoma showing the characteristic physaliphorous cells and mucinous matrix.
A higher magnification light microscopic view of a A higher magnification light microscopic view of a hematoxylin and eosin (H&E)–stained section of a chordoma showing physaliphorous cells.

Various histologic growth patterns can be seen in chordomas. Cells may be arranged in a diffuse or lobular pattern, or they may be clustered in groups or islands in a sheetlike pattern. Areas of tumor cells may be seen in a solid, perivascular, or even ribbonlike pattern. Between the cells or clusters, an abundant basophilic-to-metachromatic mucinous matrix exists. Mitoses, foci of pleomorphic cells, and focal hemorrhages are rarely seen but are not prominent features. Fibrous tissue surrounds the neoplasm and extends projections into the tumor, usually without forming a true capsule.

Poorly differentiated chordoma is a newly recognized entity in the World Health Organization (WHO) classification of tumors of soft tissue and bone. Slightly more than 60 such cases had been documented by the end of 2021.[19]  Poorly differentiated chordomas are more common among young adult and pediatric patients, as are skull base chordomas. Poorly differentiated chordomas show loss of the INI1 gene.[1]

Poorly differentiated chordomas display a spectrum of features, are associated with a lower index of suspicion for diagnosis, and involve aggressive outcomes. Critical analysis of radiologic and histopathologic features, including necessary immunostaining (brachyury and SMARCB1/INI1), is supportive of their timely diagnosis. These tumors show loss of SMARCB1/INI1 immunostaining and homozygous deletion of the INI1/SMARCB1 gene.[19]

In a case report, Curcio and coworkers suggested that loss of SMARCB1 is an early event in cases of rare conventional chordoma that could potentially evolve into poorly differentiated chordoma through additional genomic aberrations such as genome doubling. They concluded that further studies are needed to determine whether genome doubling provides a consistent pathway for evolution of poorly differentiated chordoma.[20]

Dedifferentiated chordomas typically are the fastest-growing and most aggressive chordomas; they can show loss of INI1 and are more common among pediatric patients. Chordomas have been reported to dedifferentiate into high-grade spindle cell tumors, which portend a worse prognosis.[1]  The dedifferentiated variant of chordoma is rare, accounting for 2-8% of chordomas. These can occur de novo or as a sarcomatoid transformation in recurrence of conventional chordoma, sometimes following radiation therapy.[21, 22]

The chondroid variant of chordoma is well recognized. With these tumors, a significant cartilaginous component is present, along with features of either chondrosarcoma or chondroma. Some investigators believe that these entities are separate and that studies with both immunoperoxidase staining and electron microscopy can distinguish them. Patients with this variant were once thought to have a slightly better prognosis; however, later, large studies have showed this variant to have no prognostic significance.

Chondroid chordomas are difficult to distinguish from chondrosarcomas on histology. Typically, chordomas express the gene brachyury, whereas chondrosarcomas do not express this gene.[1]  For chordoma, brachyury has been identified as a prominent biomarker and a potential molecular immunotherapy target, as well as a target of programmed death-1 (PD-1) inhibition.[23]

With specialized histochemistry, chordoma tumor cells tend to be periodic acid-Schiff (PAS) positive. The matrix stains diffusely with mucicarmine and Alcian blue, and it stains metachromatically with toluidine blue; it is negative with Sudan black.

On electron microscopy, ultrastructural features of chordoma include desmosomal attachments and prominent mucinous vacuoles.

Immunohistochemically, tumor cells label with cytokeratins and epithelial membrane antigen (EMA). Both chordomas and the embryologic notochord are S-100 positive, whereas most carcinomas are negative. This difference in S-100 positivity can be helpful in differentiating metastatic carcinomas from chordomas when the histologic pattern is similar. Positivity for cytokeratins and EMA can be helpful in distinguishing the chondroid variant of chordoma from chondrosarcoma.

Immunohistochemical and gene microarray studies have revealed the presence of high levels of brachyury in axial chordomas. Brachyury is a key transcription factor in the development of posterior mesoderm, which becomes restricted to the notochord and the tailbud. Although the classic marker—cytokeratin—remains the single best diagnostic marker for chordoma, brachyury added to the diagnostic panel slightly improves accuracy.[24]

Continuing research into the molecular pathophysiology of chordoma has led to the discovery of several pathways that may serve as potential targets for molecular therapy, including a multitude of receptor tyrosine kinases (eg, platelet-derived growth factor receptor [PDGFR], epidermal growth factor receptor [EGFR]), downstream cascades (eg, phosphoinositide 3-kinase [PI3K]/protein kinase B [Akt]/mechanistic target of rapamycin [mTOR]), brachyury—a transcription factor expressed ubiquitously in chordoma but not in other tissues, and the fibroblast growth factor (FGF)/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. Investigation and advances in the field may lead to improved outcomes for patients with this challenging disease.[10]

The role of MIB-1 immunohistochemical staining (a proliferation marker) as a prognostic indicator in chordoma is controversial, but data suggest that an increased MIB-1 labeling index correlates with recurrence.

Selection of molecular targeted inhibitors (MTIs) for patients with advanced or relapsed chordoma should be based on gene mutation screening and immunohistochemistry. Tyrosine kinase inhibitor (TKI) monotherapy is recommended as first-line management, and combination therapy (2 TKIs or 1 TKI plus 1 mTOR inhibitor) may be the choice for drug-resistant chordoma. Brachyury vaccine offers a promising therapeutic strategy; additional clinical trials are needed to evaluate its safety and efficacy.[25]

Cytologic detection of chordoma cells in the serosal cavity is challenging because of its rare presentation. Investigators reported the first case of chordoma showing malignant pleural effusion accompanied by pleuroplumonary metastases in a 68-year-old woman for whom chordoma cells were cytologically detected in pleural effusions. These findings suggest that conventional cytology combined with cell block immunocytochemistry can increase the accuracy of chordoma cell detection in the serosal cavity.[26]

An integrative analysis of clinicopathologic and molecular characteristics of dedifferentiated chordoma reported that by immunohistochemistry, the conventional/chondroid component consistently expressed cytokeratin and brachyury, whereas the dedifferentiated component showed loss of both. Further, a sacral conventional chordoma with INI1 loss was identified, with one of the lung metastases showing biphasic histology with loss of cytokeratin and brachyury in the dedifferentiated component. Sequencing revealed tumor suppressor mutations in 4 tumors, including TP53 mutations in the dedifferentiated component in 3 tumors.[27]

In summary, dedifferentiated chordoma involves diverse sites and presents de novo, post radiotherapy, or as recurrence/metastasis months to years after initial diagnosis. The dedifferentiated component shows loss of brachyury and cytokeratin staining and harbors recurrent TP53 mutations, implicating tumor suppressor dysregulation in chordoma dedifferentiation.[27]

Staging

Chordomas are localized in the axial skeleton, where they occur from the clivus to the sacrococcygeal region. They are slow-growing, locally destructive tumors that often are not diagnosed until they have reached an advanced stage.[3]

The inherent FDG avidity of chordomas suggests that 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) may be a useful modality for staging, evaluating treatment response, and assessing recurrent or metastatic disease.[28]

Age at diagnosis, tumor size, and disease stage can influence conditional survival for patients with chordoma. The hazard ratio of different factors changes over survival time. Therefore, understanding the changing risk profile and the conditional 5-year disease-specific survival (DSS) of chordoma is critical for accurate clinical treatment guidance.[29]

Patients receiving radiation therapy showed decreased survival—likely an indication of the patients' advanced stage of disease, making them poor surgical candidates.[15]

 

Treatment

Medical Therapy

Currently, there is no approved medical treatment for individuals with diagnosed chordoma. Surgical en bloc resection with negative margins is the only curative treatment for this disease. High-dose irradiation, particularly with protons and carbon ions, is a therapeutic alternative in cases of inoperable tumor. Clinical trials exploring additional therapeutic modalities are ongoing.[3]

In a systematic review of 33 studies that reported on use of molecular targeted therapy (MTT) for advanced chordoma, the investigators extracted and analyzed data on clinical outcomes, such as median overall survival, progression-free survival, response rate, and adverse events. They found that imatinib and erlotinib were the most frequently used molecular targeted inhibitors for chordoma, and that for PDGFR-positive and/or EGFR-positive chordomas, clinical benefits were achieved with acceptable adverse events. They stated that monotherapy is preferred as first-line treatment, and combined drug therapy as second-line treatment. Tyrosine kinase inhibitor (TKI) monotherapy is recommended for first-line management, and combination therapy (2 TKIs or 1 TKI plus 1 mTOR inhibitor) may be the choice for drug-resistant chordoma. Brachyury vaccine is a promising therapeutic strategy; additional clinical trials must be undertaken to evaluate its safety and efficacy.[25]

Despite the fact that surgery remains the cornerstone of treatment, total resection is not reasonable for all patients with chordoma. For this reason, adjuvant treatment is highly important to ensure local control. If the residual tumor is of small volume, stereotactic body radiation therapy (SBRT) may provide advantages.[30]  Chordoma is a chemoresistant disease; in advanced disease, imatinib has a role.

In a case report of a 48-year-old man with a sacral chordoma who underwent partial sacrectomy followed by postoperative radiotherapy, the patient received palliative radiotherapy and imatinib treatment upon recurrence. When the disease was refractory to imatinib, he was started on treatment with erlotinib, showing partial response on imaging at 2 months. As seen in previously reported cases, erlotinib is a therapeutic option in advanced chordoma, even in imatinib-refractory cases, and thus exploration of its therapeutic role in prospective clinical trials is warranted.[31]

Research is ongoing, and surgery remains the standard treatment for chordoma. Adjuvant radiation therapy is used in cases in which incomplete resection is suspected. Traditional chemotherapy has not been shown to be effective.

Surgical Therapy

Contraindications to surgery for excision of a chordoma primarily are related to general health of the patient and preexisting medical conditions. The patient should be evaluated for cardiac, pulmonary, hematologic, and endocrine disorders, as well as coagulation status. These disorders must be addressed and managed prior to surgery.

Surgical resection remains the primary mode of treatment for both diagnostic and therapeutic purposes. The prognosis for patients with chordoma generally depends on extent and completeness of tumor excision.

Success often depends on extent and location of the tumor. In general, more complete removal with wide excision delays the time interval between surgery and eventual recurrence. The natural history and the effectiveness of different types of therapy for chordoma are not well understood because of its rare incidence and slow-growing nature.

Radical resection of tumors with clean margins is associated with a longer disease-free interval. If subtotal excision is the only option (generally due to location and proximity to delicate anatomy), added radiation therapy can lengthen the interval to recurrence. In cases in which radiation therapy is utilized without surgical resection, an average of only 50% of patients attain 10-year local control of skull-based and cervical spine tumors.

Preoperative details

Imaging of the tumor prior to surgery can reveal the extent of the tumor by showing both extent of bone involvement or erosion and depth of expansion of the tumor into adjacent soft tissues. This information can be important in planning the most advantageous resection possible.

As for any surgical patient, preoperative history and physical examination are required. Other medical problems (eg, cardiovascular, respiratory) must be stabilized or addressed. Laboratory studies, including electrolytes, coagulation status, and blood count, are needed. Radiologic studies (x-ray, CT scan, MRI) can be used for both evaluation of the tumor and assessment of other medical problems. Chest radiograph, electrocardiography, and blood crossmatch may be important.

Intraoperative details

Evaluation of tumor margins is essential for assessment of the status of resection as the resection proceeds. Knowledge of the completeness of the tumor resection helps the clinician to predict patient outcomes in terms of length of the disease-free interval and to determine the need for adjunctive therapy such as radiation.

Postoperative details

General postoperative complications relevant to this or any surgery include wound infection and infection of the operative bed (abscess), shock, pulmonary complications (respiratory failure, atelectasis, infection), and bladder infection or urinary retention.

Complications particular to cranial neurosurgery include the possibility of intracranial hemorrhage, meningitis, osteomyelitis, seizures, hydrocephalus, increased intracranial pressure, hematoma formation, swollen eyelids, keratitis, and facial palsy.

Rehabilitation may be necessary in the case of sacral surgery if damage to the spinal cord has occurred and if the level of presurgical functioning requires it.

Patients with chordoma who are admitted to inpatient rehabilitation facilities after surgical tumor resection experience improvement in multiple functional domains and a high rate of acute hospital transfer, but this is comparable to that seen with other cancer rehabilitation populations. Understanding the characteristics of the postoperative chordoma population is essential for those who will direct future studies regarding cancer rehabilitation.[32]

Recovery from sacral or cranial procedures depends on extent of tumor removal and level of intraoperative injury to adjacent neural structures. Problems may include, but are not limited to, facial palsies, incontinence, and difficulty walking.

Complications occur at a higher rate after radical resection than after subtotal resection and depend somewhat on the location of the tumor.

Morbidity from surgery can be very mild or severe. With resection of sacrococcygeal chordoma, dysfunction of bowel and bladder is the most frequent complication.

 

Follow-up

Frequent follow-up is required because of the high rate of recurrence of these tumors. Tumor recurrence identified early is easier to treat. The average interval to recurrence is 3.8 years for radically resected tumors, 2.1 years for subtotal resection followed by radiation therapy, and 8 months for subtotal excision without adjuvant therapy. The interval of follow-up, including repeat MRI or CT, depends on completeness of the resection. Because residual tumor drastically shortens recurrence time, patients with known or suspected residual tumor need to be evaluated more frequently.

A retrospective single-institution study explored the usefulness of tumor growth rate (TGR) as a preoperative radiologic marker for chordoma recurrence. Tumor growth rate is an image-based calculation that provides quantitative information on changes in tumor volume over time and has been shown to predict progression-free survival in other tumor types. Researchers have concluded that TGR may be considered a preoperative radiologic indicator of tumor proliferation and seems to preoperatively identify more aggressive tumors with a higher tendency to recur. Study findings suggest that the therapeutic strategy and the clinical-radiologic follow-up of patients with chordoma can be adapted according to this new parameter.[33]

Outcome and Prognosis

Chordomas are relatively benign-appearing neoplasms; however, because of their tendency to erode bone and invade soft tissues, they usually display malignant behavior. In addition, the location of the tumor influences the ability of the surgeon to achieve complete resection. Chordomas often grow in inaccessible sites, and their margins within soft tissue often are not well defined. As a result, complete excision of chordomas is difficult at best.

Despite the low-grade status of chordomas, they have a high recurrence rate and involve significant mortality. Five-year survival is approximately 50% overall but is improved to 65% with complete resection with negative margins. Surgical resection with positive margins is associated with approximately 50% 5-year survival, and if the chordoma is inoperable, 5-year survival is approximately 40%.[1]

Multivariate analysis of a US population with chordoma revealed that older age, greater tumor size, and distant metastasis were correlated with decreased survival, whereas surgical resection was correlated with increased survival. Patients receiving radiation therapy also showed decreased survival—likely an indication of the patients' advanced stage of disease, making them poor surgical candidates.[15, 16]

Future and Controversies

Chordoma is a complex disease because of its rarity, biological heterogeneity, and peculiar clinical behavior. Despite the progress made, outcomes of this disease remain unsatisfactory, and identification of active systemic treatments remains an urgent unmet medical need. Significant steps forward have enhanced our comprehension of chordoma complexity, with insights gained into the biology and morphology of this disease. New entities have been described, and potentially druggable molecular targets identified. This is becoming all the more relevant today, as new potentially active agents are under development.[17]

With increasing prevalence of cancer survivors, improving function during and after cancer treatment is extremely important. Chordoma patients who are admitted to inpatient rehabilitation facilities after surgical tumor resection experience improvement in multiple functional domains. Chordoma patients admitted to inpatient rehabilitation facilities experience a high rate of acute hospital transfer, but this is comparable to that of other cancer rehabilitation populations. Understanding the characteristics of the postoperative chordoma population is essential for those who will direct future studies regarding cancer rehabilitation.[32]

Castiglione and associates described a combined one-stage robot-assisted sacral chordoma resection. They reported that the tumor was en bloc removed by a combined one-stage anterior laparoscopic robot-assisted and posterior open lumbosacral approach with continued intraoperative neurophysiologic monitoring of sacral and pudendal plexuses in a 64-year-old woman with a histologic diagnosis of chordoma. After surgery, the patient reported pain relief and total recovery of bowel function, with good 11-month follow-up outcomes. Researchers concluded that this combined technique represents a promising treatment option in selected cases. The robotic technology combined with the experience of highly qualified staff can improve surgical results by minimizing complications. However, longer follow-up is needed to confirm the long-term effects of this approach in terms of recurrence and survival.[34]

Results of an in vitro and in vivo investigation of the effects of SMARCB1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1) on chordoma cells reveal that the SMARCB1/ATG5 axis is a promising therapeutic target for chordoma, and autophagy inhibitors may be effective agents for chordoma treatment.[35]

Chen and colleagues examined the role of glycogen synthase kinase 3 beta (GSK-3β) in the development of chordoma. Through methods that consisted of immunohistochemistry, Western blotting, immunofluorescence, real-time quantitative reverse transcription (qRT)-polymerase chain reaction (PCR), CCK-8 assay, and colony formation analysis, among others, they concluded that the GSK-3β-P21 axis may be an important signaling pathway for the occurrence and development of chordoma, providing a new therapeutic target for clinical treatment of patients with this disorder.[36]

For the present, the mainstay of therapy for chordoma remains primary surgical excision, with radiation therapy added for incompletely resected tumors. The near future will likely see the confirmation of potential therapeutic targets, such as signaling molecules in the pathways mentioned above. Inhibitors of these pathways may then be used to arrest the progression of disease, especially for patients with incomplete resection or recurrent/metastatic disease.[37]

Although these molecular studies continue to explore new treatment modalities for chordoma, the most significant dilemma remains the choice between a radical surgical procedure with the potential for serious morbidity and a subtotal resection with increased potential for recurrence. The general health of the patient should be considered during planning for the surgical procedure. With explanations of the risks and benefits provided to the patient, an informed decision regarding therapy can be reached.

 

Guidelines

Guidelines Summary

Guidelines Contributor: Mrinal M Gounder, MD, Attending Physician in Medical Oncology, Sarcoma and Developmental Therapeutics Service, Memorial Sloan-Kettering Cancer Center

Guidelines for the management of chordoma have been published by the following organizations:

  • National Comprehensive Cancer Network (NCCN) [38, 39]
  • European Society for Medical Oncology (ESMO) [40, 41]

NCCN Guidelines

NCCN recommendations for treatment of chordoma are as follows[38, 39] :

  • Enrollment in a clinical trial should be considered when available; in addition, when possible, patients should be referred to a tertiary care center with expertise in sarcoma, for treatment by a multidisciplinary team.
  • Wide excision with or without radiation therapy should be provided for tumors of the sacrum and mobile spine.
  • Intralesional excision with or without radiation therapy may be the best feasible treatment for resectable skull base tumors when wide excision is not possible; re-resection can be considered with positive surgical margins; postoperative radiation can improve local control.
  • Adjuvant radiation therapy can be considered for large tumors or for positive surgical margins after resection.
  • Radiation therapy is the primary treatment for unresectable tumors regardless of location.
  • Dedifferentiated chordomas are treated according to soft tissue sarcoma management guidelines; chemotherapy can be provided when clinically indicated.
  • For local recurrence, surgical excision should be performed with or without radiation therapy and/or chemotherapy.
  • For metastatic disease, options include chemotherapy and/or surgical excision and/or radiation therapy and/or best supportive care.

Conventional or Chondroid Chordoma

National Comprehensive Cancer Network (NCCN) guidelines (2020) recommend that all patients with conventional or chondroid chordoma should be evaluated and treated by a multidisciplinary team of doctors who are experts in the management of chordoma. They should undergo the following tests before treatment is begun[38] :

  • Medical history and physical exam
  • Imaging of primary site that might include x-ray, computed tomography (CT) and/or magnetic resonance imaging (MRI), as well as screening MRI of the spine
  • Chest/abdominal/pelvic CT with contrast
  • Positron emission tomography (PET)/CT (skull base to midthigh)
  • Bone scan (should be considered)

Treatment options may include surgical excision and/or radiation therapy and/or systemic therapy, along with best supportive care.

Systemic therapy options may include use of imatinib, dasatinib, sunitinib, cisplatin or sirolimus, erlotinib, lapatinib (for epidermal growth factor receptor [EGFR]-positive chordoma), and sorafenib, given alone or in combination.

The finding of other lesions indicates a non-bone primary tumor. If no other lesions are found, the patient should be referred to an orthopedic oncologist for biopsy.

Poorly Differentiated or Dedifferentiated Chordoma

For those with poorly differentiated or dedifferentiated chordoma, practitioners can refer to the NCCN Guidelines for Soft Tissue Sarcoma (2020), which recommend the following[39] :

General health testing

  • Medical  history
  • Family history
  • Physical exam

Imaging tests

  • MRI
  • CT
  • PET scan
  • X-ray
  • Ultrasonography
  • Angiography

Tissue testing

  • Fine-needle aspiration
  • Core needle biopsy
  • Incisional biopsy

Genetic testing (should be considered)

Cancer staging

  • Tumor-node-metastasis (TNM) scores
  • Cancer grade
  • Disease stage

Treatment options may include surgery, radiation therapy, and other local treatments.

Systemic therapy options may include chemotherapy, targeted therapy, and immunotherapy.

ESMO Guidelines

ESMO guidelines are in general agreement with NCCN guidelines.[38, 39, 40, 41]

Over many years, experts had not reached consensus regarding appropriate clinical management of chordoma, resulting in inconsistent care and suboptimal outcomes for many patients. To address this shortcoming, the European Society of Medical Oncology (ESMO) and the Chordoma Foundation (CF)—the global chordoma patient advocacy group—convened a multidisciplinary group of chordoma specialists to define by consensus evidence-based best practices for the optimal approach to chordoma. In January 2015, the first recommendations of this group were published. In November 2015, ESMO and CF convened a second consensus group, including specialists from Europe, the United States, and Japan with expertise in treatment of patients with chordoma.[40, 41]

ESMO best practices for management of local-regional recurrent chordoma recommend follow-up of an abnormal radiograph with contrast-enhanced magnetic resonance imaging (MRI) of the whole compartment with adjacent joints. In addition, restaging with total body computed tomography (CT) and whole spine MRI and a thorough clinical examination should complement locoregional assessment to rule out distant metastases and/or subarachnoid spread.[40, 41]

Surgical and radiation therapy (RT) strategies should be guided by the nature and extent of the previous procedure, the location of the recurrence, tumor resectability, deliverability of RT, and the expected morbidity of each procedure. Other relevant factors include age, comorbidity, performance status, and status of surrounding tissues including the skin.

Retrospective data suggest that cryoablation and radiofrequency ablation (RFA) can be safe and useful palliative treatments in recurrent chordoma, providing pain control benefit. Stereotactic body radiation therapy (SBRT) has been suggested as a palliative treatment option, but prospective confirmatory data are needed. In principle, other local therapies such as local microwave hyperthermia and high-intensity focused ultrasound (HIFU) may offer benefit in a palliative setting; however, no published data are available to support their use.

Medical therapy options are limited, and no drugs are approved for treatment of advanced chordoma. Several targeted therapies have shown modest activity in patients with recurrent disease. Imatinib and sorafenib are the agents with greatest evidence of efficacy in advanced chordoma and represent reasonable palliative treatment options to slow disease progression or alleviate symptoms.

Cytotoxic chemotherapy is generally inactive, and evidence is insufficient to recommend it. No predictors of response to targeted agents have been identified, but one potentially relevant biomarker is loss of INI1, which has been reported in dedifferentiated chordoma and may confer sensitivity to EZH2 inhibitors.

Worsening of somatic and neuropathic pain and/or worsening neurologic symptoms can be the first sign of disease relapse/progression, even when this cannot be detected radiologically.

First-line analgesic therapy should be provided according to available guidelines.

In the terminal phase, the patient’s preferred setting of care should be identified. Hospice and home care are valid options.

Palliative care should be considered as part of the active management of all patients and should include pain and symptom control, discussion about a patient’s concerns and wishes, conversation about advanced directives, and evaluation of patient and family psychosocial needs.

Guidelines summary

Both NCCN and ESMO guidelines state that biopsy is required to confirm the diagnosis prior to any surgical procedure and should be performed at a specialized center that will provide definitive treatment.[38, 39, 40, 41]

For patients with unsuccessful surgery and RT, there remains an urgent unmet need for new therapeutic options. To facilitate patient participation in clinical trials, the Chordoma Foundation maintains an up-to-date list of trials open to chordoma patients (www.chordomafoundation.org/clinical-trials/) and a target dashboard (www.chordomafoundation.org/targets/) summarizing published data about therapeutically relevant targets.