Chordoma

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: Notochordoma; chordocarcinoma; chordoepithelioma

Overview

Chordoma is a rare bone cancer that is diagnosed in only about 300 patients in the U.S. each year. Chordoma accounts for 1% of intracranial tumors and 4% of all primary bone tumors. It develops at the base of the skull, in a vertebra, or at end of the spine (in the sacrum or the coccyx) with about equal frequency. The cells that give rise to chordoma come from the notochord. The notochord is an important structure in the early embryo that disappears before birth. However, even after birth, some cells from the notochord remain in bones at the base of the skull, in vertebrae, and in the tail bone. Rarely, one of these cells, which are called notochord remnants, undergoes changes that give rise to a chordoma. They originate from embryonic remnants of the primitive notochord (earliest fetal axial skeleton, extending from the Rathke's pouch to the coccyx). Since chordomas arise in bone, they are usually extradural and result in local bone destruction.

Pathophysiology

Gross Pathology

• Fluid and gelatinous mucoid substance (associated with recent and old haemorrhage) and necrotic areas are found within the tumor.
• In some patients, calcification and sequestered bone fragments are found as well.

Microscopic Pathology

• Histologically, chordomas are categorized as classical (or conventional), chondroid, and dedifferentiated.
• The first microscopic characterization of chordomas dates back to 1857, when Virchow first identified the cells typical of this tumor and described them as “physaliferous” (Greek for “bubble-bearing”) because of the foamy appearance of their cytoplasm that contains multiple vacuoles.
• Ultrastructural studies have indicated that the vacuoles can be divided into two subtypes, smooth-walled and villous, based upon the absence or presence of microvilli, respectively.
• Physaliferous cells are typical of classical chordomas, appearing as groups of gray-white large cells separated by fibrous septa into lobules and surrounded by a basophilic extracellular matrix rich in mucin and glycogen.
• Chondroid chordomas show histological features resembling both chordoma and chondrosarcoma, a malignant tumor of the bone and soft tissue.
• This histological variant accounts for 5%–15% of all chordomas and up to 33% of all cranial chordomas, being preferentially found on the spheno-occipital side of the skull base.
• Despite an appearance that resembles hyaline cartilage, these tumors retain an epithelial phenotype and express specific chordoma markers, including cytokeratin and S-100, which are not found in cartilaginous tissue; this has suggested their alternative, more appropriate classification as “hyalinized chordomas”.
• Dedifferentiated chordomas are also rare, 10% of chordomas, and are characterized by sarcomatous regions, which are comprised of spindle-shaped polygonal cells.

Genetics

• Recent genetic analysis of chordoma using high-resolution array Comparative genomic hybridization in tumor samples from patients with familial chordoma revealed unique duplications in the 6q27 region.
• Interestingly, the duplicated region only contained the T (brachyury) gene, which was previously found to be uniquely overexpressed in almost all sporadic chordomas compared with other bone or cartilaginous lesions.
• Brachyury regulates several compelling stem cell genes and has recently been implicated in promoting epithelial-mesenchymal transition in other human carcinomacarcinomas.
• Although it is still not clear what role brachyury plays in the pathogenesis of chordomas, the identification of the duplication and the remarkable overexpression seen in samples suggest that it may be a critical molecular driver in the initiation and propagation of this cancer.

Classification

Chordoma may be classified into three subtypes based on location of the tumor along the spine: clival (or skull-base), sacrococcygeal, cervical, thoracic, and lumbar. Chordomas are relatively evenly distributed among three locations:

Sacrococcygeal

This is the most common location, accounting for approximately 30-50% of all chordomas and involving particularly the fourth and fifth sacral segments. In this location a male predilection has been reported (M:F ratio of 2:1) and the tumor may be particularly large at presentation.

Skull-base

The clival region is the next most common, accounting for 30-35% of cases. Typically the mass projects in the midline posteriorly indenting the pons. This characteristic appearance has been termed the "thumb sign".

Vertebral bodies

Chordomas of the vertebral bodies are rare but after lymphoproliferative tumors are nonetheless the most common primary malignancy of the spine in adults. They most commonly involve the cervical spine (particularly C2), followed by the lumbar spine then the thoracic spine. They often extend across the intervertebral disc space, involving more than one vertebral segment. They may extend into the epidural space, compressing the spinal cord, or along the nerve roots, enlarging the neural exit foramen.

Differential Diagnosis

Clival Chordoma must be differentiated from other diseases such as:

• Chondrosarcoma of skull base
• Plasmacytoma
• Meningioma of skull base
• Pituitary macroadenoma
• Ecchordosis physaliphora

Vertebral Chordoma must be differentiated from other diseases such as:

• Chondrosarcoma
  • Neural arch > vertebral body
  • Thoracic spine is the most commonly involved spinal region
  • Chondroid matrix (rings & arcs)
  • Similar MRI appearance to chordomas (low to intermediate signal intensity on T1, hyperintense on T2, enhances)

• Giant cell tumor
  • Location: sacrum > thoracic spine > cervical spine > lumbar spine
  • No mineralised matrix
  • Heterogeneous intermediate to hyperintense T2 signal

• Spinal metastases
  • Hypointense on T1; variably hyperintense on T2
• Often multiple, involving vertebral bodies and posterior elements

• Plasmacytoma
  • Destructive vertebral body lesion (similar appearance to lytic metastases)

• Spinal lymphoma
  • Multifocal disease
  • Heterogenous T2 signal

Epidemiology

Chordomas are very rare tumors that affect approximately one in a million individuals. Chordoma represents up to 4% of primary malignant bone tumors and 20% of primary spine tumors.

Incidence

• The overall incidence of chordoma is approximately 0.1 per 100,000 individuals in the United States.

Age

• Chordomas may appear at any age, but are most commonly noticed among patients older than 30 years of age.
• The median age at presentation for cranial chordomas is in the sixth decade, slightly younger for sacral chordomas, and with rare occurrences in the pediatric population.
• Chordomas in children and adolescents account for <5% of all chordoma cases.

Gender

Men are more commonly affected with chordomas than females.

Prognosis

• Prognosis of chordoma is typically poor, due to the locally aggressive nature of these tumors, with the 10-year survival approximately 40%.
• The median survival of cranial base chordomas is estimated at 6.29 years, with 5-year overall survival and progression-free survival rates of 78.4% and 50.8%, respectively.
• The lethality of skull-base chordoma is largely due to local progression, although systemic metastasis has been reported in 12.5% of skull base tumors.

Complications

• Chordoma does not usually spread to other bones but can recur after treatment.
• Metastatic spread of chordoma is observed in 7-14% of patients and includes nodal, pulmonary, bone, cerebral or abdominal visceral involvement, predominantly from massive tumors.
• Incomplete delineation of the tumor and microscopic distal extension of tumor cells may explain the frequency of recurrences.

Diagnosis

X Ray

• Conventional X-rays show irregular and expansile vertebrae as a result of the destructive, slow-growing, and reactive bone-forming nature of the tumor

CT

Findings on CT scan suggestive of chordoma include:

• Centrally located well-circumscribed destructive lytic lesion
• Marginal sclerosis
• Expansile soft-tissue mass (usually hyper-attenuating relative to the adjacent brain; however, inhomogenous areas may be seen due to cystic necrosis or hemorrhage; the soft-tissue mass is often disproportionately large relative to the bony destruction)
• Irregular intratumoral calcifications (thought to represent sequestra of normal bone rather than dystrophic calcifications)
• Moderate to marked enhancement

MRI

On MRI, chordoma is characterized by calcifications and bony expansion. MRI image characteristics observed among chordoma patients include:

• T1:
  • Intermediate to low signal intensity
  • Small foci of hyperintensity (intratumoral hemorrhage or a mucus pool)

• T2:
  • Most exhibit very high signal

• T1 C+ (Gd):
  • Heterogeneous enhancement with a honeycomb appearance corresponding to low T1 signal areas within the tumor
  • GE (gradient echo): confirms hemorrhage if present with blooming

Treatment

Traditionally surgical resection has been the first line of treatment for chordoma in feasible scenarios, with radiotherapy offered for recurrent cases.

Medical Therapy

Chemotherapy

• Chemotherapy for chordomas usually results in low response rates.
• Only a few clinical series have reported the use of chemotherapy for managing chordoma, which is generally used in the latter course of the disease and only as palliative treatment.

Radiotherapy

• Chordomas are relatively radioresistant, requiring high doses of radiation to be controlled.
• The proximity of chordomas to vital neurological structures such as the brain stem and nerves limits the dose of radiation that can safely be delivered. *Therefore, highly focused radiation such as proton therapy and carbon ion therapy are more effective than conventional x-ray radiation.

Surgery

• The principal goals of surgery include:
  • Histologic confirmation of the lesion
  • Achieve a maximal safe resection
  • Provide symptomatic improvement
  • Facilitate adjuvant treatment such as radiotherapy, by minimizing the treatment volume and maximizing the distance between the target volume and critical surrounding neurovascular structures.
• Wide en bloc resection with adequate bone and soft tissue margins is the primary surgical goal.
• However, sometimes, wide margins are very difficult to attain because these tumors are located at sites that are difficult to access, with high rates of complications and sequelae.
• Percutaneous radiofrequency ablation has been trialled as an adjunct.

References

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