Chordoma 

Updated: Nov 10, 2016
Author: Cheryl Ann Palmer, MD; Chief Editor: Brian H Kopell, MD 

Overview

Background

Chordomas are rare tumors that arise from embryonic notochordal remnants along the length of the neuraxis at developmentally active sites. These sites are the ends of the neuraxis and the vertebral bodies. Chordomas constitute less than 1% of CNS tumors and rarely occur in extra-axial locations. Chordomas are thought to arise from ectopic notochord remnants. Chordomas are optimally managed with aggressive surgery, while preserving key structures, and postoperative radiation.[1]  Chordomas are associated with significant morbidity because of their growth patterns and surgical constraints in resection.[2]

An image depicting a chordoma can be seen 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 Procedure

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.

Problem

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."[3, 4] 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.

Although chordomas are usually slow-growing tumors, they are locally aggressive with 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

Chordomas are rare neoplasms. As primary intracranial neoplasms, they only constitute 0.2% of all CNS tumors; however, they constitute 2-4% of all primary bone neoplasms. Chordomas generally occur in 3 locations, which are, in descending order of frequency, the sacrum, intracranially at the clivus, and along the spinal axis. Fifty percent of chordomas occur in the sacrum, while spinal axis chordomas are rare. Occasional parasellar and sellar examples have been described, and extraaxial sites have been reported in the literature.

When considering all locations, the male-to-female ratio is 2:1. However, skull base tumors, as a subgroup, tend to have a more equal sex distribution.

A number of reports indicate that chordomas are seen in all age groups, with the peak incidence varying by site. Intracranial chordomas present in a much younger age group than their spinal counterparts because the relevant anatomy of the clival region produces earlier symptomatology.[5, 6] In one series of chordomas reviewed, the average age at diagnosis of all patients with chordomas was 56 years, with an age range of 27-80 years. When considered by site, the average age for intracranial chordomas is 48 years; as a subgroup, chordomas of the sphenoccipital area have an average occurrence age of 38 years. The average age for sacrococcygeal chordomas is 56 years. For chordomas occurring along the vertebrae, the average age is 46 years.

In a review of demographic and clinical data of pediatric patients 19 years or younger abstracted from the Surveillance, Epidemiology, and End Result (SEER) database, pediatric primary chordomas presented most often as small tumors less than 4 cm in the cranium. Survival among pediatric patients who underwent surgery was significantly longer than for adults (22.5 vs 14.3 yr; P< 0.001), and overall survival was longer (17.2 vs 12.6 yr). Overall mortality was lower in pediatric patients (38.4 vs 49.8%), but cancer-specific mortality was higher (37.2 vs. 28.6%).[7]

Etiology

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 at 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.

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.[8] All have been implicated in the pathogenesis of chordomas. Also, microsatellite instability resulting from DNA mismatch repair deficiencies has been demonstrated; however, no chordoma-specific translocations have been identified.

In a study of 287 chordomas in 111 patients, expressions of a variety of markers were identified, including  EGFR, pSTAT3, VEGF, and mTOR pathway proteins in 85.9%, 79.1%, 85.7%, and 46%, respectively.[9]  In another study, 3 different variants accounting for 11 point mutations in 3 cancer-associated genes (KIT, KDR, and TP53) were detected.[10]

Pathophysiology

Chordomas are characterized by slow growth, with local destruction of the bone and extension into the adjacent soft tissue. Very rarely, distant metastases are encountered. These tumors usually have a relatively indolent but prolonged course with multiple local recurrences. Eventually, they may be responsible for mortality.

Presentation

The clinical presentation is entirely dependent on the location of the chordoma.[11] At the sacrum, common presenting symptoms are back and/or lower extremity pain. About one half of patients with chordomas have autonomic symptoms, particularly rectal dysfunction or urinary incontinence. About one half of patients with chordomas have a palpable sacral mass.

With intracranial tumors, the most common presenting symptoms are diplopia and headache. Neurologic signs also occur in over one half of the patients, primarily as cranial nerve palsies. Palsies of cranial nerve VI and the sensory branch of V are the most common.

Uncommon clinical presentations of intracranial tumors include CSF rhinorrhea, nasal obstruction, nasal bleeding, and subarachnoid hemorrhage.[12]

Patients with tumors located along lower vertebrae may present with pain, bladder dysfunction, or lower extremity weakness. 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. The time span from the onset of symptoms to diagnosis averages 10 months.

Indications

Surgical therapy for these tumors is indicated as they continuously grow, albeit slowly, and erode bone and adjacent soft tissue, causing marked destruction of surrounding tissues.

A meta-analysis by Di Maio et al confirmed that both 5-year progression-free survival and overall survival of skull-base chordomas are enhanced by complete resection of the tumor.[13] Furthermore, this analysis suggests that the addition of adjuvant radiation therapy is of no additional benefit to total surgical resection, but is warranted in cases of incomplete resection. No differences were found in overall survival between the different types of adjuvant radiation therapy.[13]

In a more recent retrospective case series of primary sacral chordomas that were treated with carbon ion therapy or proton therapy, Mima et al showed an improved local control of the tumor growth and a significant improvement for overall survival.[14]

Relevant Anatomy

The location of chordomas along the spinal canal is directly related to the location of notochord remnants, particularly at the ends of the spinal axis. Of chordomas, 49% occur at the sacrococcygeal region, and 30% occur at the sphenoccipital region, with nearly all of these occurring at the clivus. These tumors have a variable extension. Vertebral chordomas account for only 15% of total chordomas and occur in the lumbar, cervical, and thoracic regions in descending order of frequency.

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 they are located in bone.

Contraindications

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, hematological, or endocrine disorders as well as coagulation status. These disorders need to be addressed and managed prior to surgery.

Prognosis

Skull base chordomas (SBCs) are rare dysembryogenetic invasive tumors with a variable tendency for recurrence. In one study, the 5- and 10-year overall survival rates were 67% and 57%, respectively, and the 5- and 10-year progression-free survival rates were 58% and 44%, respectively. Extent of resection, adjuvant radiation therapy, and absence of rhinopharynx invasion were positive independent predictors of overall survival. Adjuvant radiation therapy, absence of rhinopharynx invasion, and younger patient age were positive independent predictors of progression-free survival.[15]

 

Workup

Laboratory Studies

No laboratory studies are required for the evaluation of chordomas, except as needed for routine preoperative evaluation in patients scheduled to undergo surgical resection.

Imaging Studies

CT scan or MRI studies are indicated to evaluate the extent of the tumor and to identify the tissues that the chordoma has infiltrated. Knowledge of the extent of the tumor is important in planning the optimal surgical approach.

With CT scans, chordomas at any site appear as single or multiple areas of decreased attenuation within the clivus, vertebrae, or sacrum. Fingers of low density radiate throughout the mass and into the adjacent tissues. If the chordoma has a significant chondroid component, focal regions of hyperdensity may be present. The lesions are expansile with destructive or lytic lesions in the bone.

On MRI, the appearance of a chordoma is similar to the appearance on CT scan, with better resolution of the soft-tissue component, resulting in better anatomical 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.

Plain radiographs may be useful to demonstrate the amount of bone involvement. Plain-film radiographs may show an ill-defined endosteal margin or a bulky mass in the soft tissue. The lesions also may be lytic. In general, and especially in clival chordomas, erosion of the bone, particularly the tip of the clivus, and a sclerotic bone reaction are seen radiographically. The mass appears as a destructive well-demarcated lesion. The discovery of these features can better clarify the diagnosis of chordomas in the differential of bony lesions.

Diagnostic Procedures

Imaging techniques of the clivus usually demonstrate features adequate for differentiating chordomas from other site-specific lesions. In the sacrum, radiographic features are more similar to other common bone tumors and while 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) is the preferred method for establishing the preoperative morphologic diagnosis of chordoma and has been reported to lower local recurrence rates when compared with open biopsy.[16] The 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.

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

Histologic Findings

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

Microscopically, conventional chordomas are composed of uniform cells with small oval or round eccentric nuclei and dense chromatin. The hallmark microscopic features of chordomas are the numerous, variably sized vacuoles located in the tumor cell cytoplasm, the 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. The 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, or focal hemorrhage rarely can be seen but are not prominent features.

Fibrous tissue surrounds the neoplasm and extends projections into the tumor, usually without forming a true capsule.

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

The dedifferentiated variant of chordoma is rare, comprising 2-8% of chordomas. These can occur de novo, or as a sarcomatoid transformation in recurrences of conventional chordoma, sometimes following radiation therapy.[17, 18]

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.

In electron microscopy, ultrastructural features in chordomas include desmosomal attachments and prominent mucinous vacuoles.

Immunohistochemically, the 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 the differentiation of metastatic carcinomas from chordomas in instances where 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 tailbud. Although the classic marker, cytokeratin, remains the single best diagnostic marker for chordoma, the addition of brachyury to the diagnostic panel slightly improves accuracy.[19]

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

Recent investigations have looked at cell cycle alterations and the role of the p53 tumor suppressor gene in chordoma tumorigenesis. Early data suggest that p53 overexpression characterized by increased immunohistochemical staining for p53 protein is associated with a poor prognosis in patients with chordoma.[20]

Staging

Chordomas, like other bone tumors, have been subject to staging methods. Studies analyzing the prognosis and outcome in comparison to stage have not proven to be very useful. As discussed above, the local extent and degree of resection are much more important to the prognosis of a chordoma (see Problem).

 

Treatment

Medical Therapy

A multicenter phase II clinical trial has confirmed the clinical efficacy of imatinib mesylate in the treatment of chordoma.[21] Treatment with imatinib was successful in stabilizing tumor growth (84%) or shrinking tumor size (16%) in a cohort of patients with progressing, advanced chordoma. Imatinib is a tyrosine kinase inhibitor targeting several enzymes including platelet-derived growth factor receptor–β (PDGFRB), which can be expressed in chordomas.

A combination of bevacizumab (an antivascular agent) and erlotinib (an epidermal growth factor receptor [EGRF] inhibitor) showed promising long-lasting control of chordoma growth.[22]

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

Surgical Therapy

Surgery is the preferred treatment for chordomas. Success often depends on the extent and location of the tumor. In general, a more complete removal with wide excision delays the time interval between surgery and eventual recurrence. The natural history and the effectiveness of different kinds of therapy are not well understood in chordomas because of their rare incidence and slow-growing nature.

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

Preoperative Details

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

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

Intraoperative Details

The evaluation of tumor margins is essential to assess the status of the resection as the resection proceeds. Knowledge of the completeness of the tumor resection helps predict patient outcome in terms of the length of the disease-free interval and assists in determination of the need for adjunctive therapy such as radiation.

Postoperative Details

General postoperative complications relevant to this or any surgery include wound infection or 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 possibilities 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 surgeries, if damage has occurred to the spinal cord and depending on the level of presurgical functioning.

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

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 scans, depends on the completeness of the resection. Because residual tumor drastically shortens the recurrence time, patients with known or suspected residual tumor need to be evaluated more frequently.

Complications

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

Morbidity from surgery can be either very mild or severe following tumor resection. With the resection of sacrococcygeal chordomas, bowel and bladder dysfunction are the most frequent complications.

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 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.

The 5-year survival rate is estimated to be 51%, and the 10-year survival is estimated to be 35%. Factors that may improve prognosis are young age, complete resection, and the addition of radiation and/or medical therapy in incompletely resected tumors.

Future and Controversies

Several research groups are pursuing the identification of biomarkers of chordoma that may serve as prognostic indicators as well as potential therapeutic targets. A British research group has demonstrated the activation of the mTOR-signaling pathway in about 65% of chordomas, suggesting that mTOR inhibitors such as rapamycin and its analogues might be effective.[23] Preliminary confirmation of this has come from an Italian group that treated progressive advanced chordoma with a combination of imatinib and sirolimus (a rapamycin analogue), inducing one partial response as well as stabilizing the disease in 7 patients.[24] Only one patient showed continued progression over the 9-month treatment period. Other medical therapeutic pathways have also been explored, with encouraging results (eg, a combination of bevacizumab (an antivascular agent) and erlotinib (an epidermal growth factor receptor [EGRF] inhibitor).[22]

A Harvard research group has demonstrated that the signaling molecule Stat3 (signal transducers and activators of transcription 3) expression correlated with survival and severity of disease in 70 chordoma samples.[25] Furthermore, 3 chordoma cell lines exposed to SD-1029, an inhibitor of Stat3 activation, demonstrated inhibition of in vitro phosphorylation and cellular proliferation. This inhibition was enhanced when SD-1029 was combined with chemotherapeutic agents.

For the present, the mainstay of therapy for chordoma remains primary surgical excision, with the addition of radiation therapy 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 in patients with incomplete resections or recurrent/metastatic disease.[26]

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 an 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) [27]
  • European Society for Medical Oncology (ESMO) [28]

Diagnosis

National Comprehensive Cancer Network (NCCN) guidelines recommend that all patients younger than 40 years with abnormal radiographs be referred to an orthopedic oncologist for further workup that includes biopsy. For patients 40 years of age or older, the recommended workup includes the following[27] :

  • Computed tomography (CT) of the chest, abdomen, and pelvis
  • Bone scan
  • Mammogram and other imaging studies as clinically indicated

Findings 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 a biopsy.[27]

European Society for Medical Oncology (ESMO) guidelines recommend follow-up of an abnormal radiograph with magnetic resonance imaging (MRI) of the whole compartment with adjacent joints. CT scan is recommended only in the case of diagnostic problems or doubt, to provide clearer visualization of calcification, periosteal bone formation, or cortical destruction.[28]

Both guidelines agree that biopsy is required to confirm the diagnosis prior to any surgical procedure and should be performed at a specialized center that will provide the definitive treatment.[27, 28]

Classification

ESMO guidelines recommend specifying the tumor type and subtype according to the 2013 World Health Organization (WHO) classification.[28] Under the WHO classification system, tumors are further classified as benign, intermediate, or malignant. Bone sarcomas are classified by group (eg, chondrogenic, osteogenic, fibrohistiocytic, Ewing sarcoma) and further subtyped within each group.[29]

NCCN guidelines recommend that the final pathologic evaluation include assessment of surgical margins as well as the size/dimensions of tumors.[27]

With patients who present with locally advanced or metastatic chondrosarcoma, chordoma, or osteosarcoma, physicians should discuss the options surrounding deep-sequencing genomic tests, which may identify mutations that may be responsive to specific therapies and thus may guide referral to clinical trials. Use of these tests is not part of current NCCN guidelines but is increasingly part of oncologic practice. A further barrier is that even when available, these tests are typically not reimbursed by private or government insurance.

Grading and Staging Systems

A number of staging systems are used for bone tumors. The ESMO guidelines do not provide a specific recommendation for which system should be followed.[28]  NCCN follows both the tumor-node-metastasis (TNM) classification of the American Joint Cancer Committee/Union for International Cancer Control (AJCC/UICC)[30] and the Surgical Staging System from the Musculoskeletal Tumor Society (MTS)[31] for staging.[27]

Treatment

NCCN recommendations for treatment of chordoma are as follows[27] :

  • Enrollment in a clinical trial should be considered when available; in addition, whenever 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 for tumors of the sacrum and mobile spine.

  • Intralesional excision with or without radiation therapy is the preferred treatment for resectable skull base tumors; re-resection can be considered with positive surgical margins; postoperative radiation for improved local control.

  • Adjuvant radiation therapy can be considered for large extracompartmental 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.

  • For local recurrence, surgical excision 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.

  • ESMO guidelines are in general agreement with the NCCN guidelines.[28]