Chordoma
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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.
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.” [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.
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]
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]
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.
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.
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]
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 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.
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]
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Cheryl Ann Palmer, MD Professor of Pathology, Director of Neuropathology, Director of Pathology Residency Program, Department of Pathology, Huntsman Cancer Institute, University of Utah School of Medicine
Cheryl Ann Palmer, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuropathologists, Society for Neuro-Oncology, International Society of Neuropathology
Disclosure: Nothing to disclose.
James Robinson Hackney, MD Neuropathology Fellow, Department of Pathology, University of Alabama at Birmingham School of Medicine
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Ryszard M Pluta, MD, PhD Associate Professor, Neurosurgical Department Medical Research Center, Polish Academy of Sciences, Poland; Clinical Staff Scientist, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH); Fishbein Fellow, JAMA
Ryszard M Pluta, MD, PhD is a member of the following medical societies: Polish Society of Neurosurgeons, Congress of Neurological Surgeons
Disclosure: Nothing to disclose.
Brian H Kopell, MD Associate Professor, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai
Brian H Kopell, MD is a member of the following medical societies: Alpha Omega Alpha, American Association of Neurological Surgeons, American Society for Stereotactic and Functional Neurosurgery, Congress of Neurological Surgeons, International Parkinson and Movement Disorder Society, North American Neuromodulation Society
Disclosure: Received consulting fee from Medtronic for consulting; Received consulting fee from Abbott Neuromodulation for consulting.
Duc Hoang Duong, MD Professor, Chief Physician, Departments of Neurological Surgery and Neuroscience, Epilepsy Center, Charles Drew University of Medicine and Science
Duc Hoang Duong, MD is a member of the following medical societies: American Neurological Association, Congress of Neurological Surgeons, North American Skull Base Society
Disclosure: Nothing to disclose.
The authors wish to acknowledge the contributions of Daniel Keith Harrison, MD, to prior versions of this article.
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