General
- Chordomas are a family of primary malignant bone neoplasms that demonstrate notochordal differentiation.
- This family includes conventional, chondroid, poorly differentiated, and dedifferentiated types.
Definition
- Essential criteria
- Location as a midline axial bone tumour.
- Histological presence of lobules containing cohesive and physaliphorous cells within a myxoid or chondroid matrix.
- Positive immunohistochemical expression of brachyury.
- Criteria for specific forms
- For poorly differentiated chordoma (epithelioid or solid forms), the loss of SMARCB1 (INI1) expression is essential for confirmation.
Numbers
- Annual incidence of approximately 0.088 cases per 100,000 person-years.
- 0.5% of all primary central nervous system (CNS) tumours.
- Most common primary bony spinal tumour (2nd most common is osteosarcoma)
- Myeloma is the most common primary malignancy of bone (i.e. all bones)
- Any age
- Most common: 40 - 60 year old
- Children and young adults: usually cranial chordoma
- Children with Tuberous sclerosis have a higher incidence of Chordoma
- Male predominance (2:1)
- Age and sex distribution vary by histopathological type:
- Conventional chordoma: Median age of 55 years; primarily affects adults (96%); male-to-female ratio of 1.7.
- Chondroid chordoma: Median age of 45 years; primarily affects adults (86%); male-to-female ratio of 1.1.
- Dedifferentiated chordoma: Median age of 61 years; primarily affects adults (96%); male-to-female ratio of 1.8.
- Poorly differentiated chordoma: Median age of 7 years; primarily affects children (86%); male-to-female ratio of 0.7.
Localisation
- Where notochord was located
- Intraosseous: > 95% of cases (usually axial skeleton)
- Sacrococcygeal: 30-50%
- Spheno-occipital (Clival): 30-35%
- Vertebral body: 15-30%
- Rare
- Extra-axial skeleton
- Soft tissue (chordoma periphericum)
- Distribution varies by type:
- Conventional chordomas: Sacrococcygeal region (55%)
- Chondroid: skull base (73%)
- Poorly differentiated: skull base (64%)
Cell origin
- Embryological remnants of the notochord
Grading
- Slow growing but destructive lesions
- Malignant tumour at the primary site.
Histopathology
Macroscopy
- Expansile lobulated mass that usually permeates the cortex and invades adjacent soft tissue
- 5 - 15 cm in greatest dimension
- Cut surface is gelatinous to chondroid
Microscopy
- Infiltrative border
- Low power architecture is lobular, with fibrous bands separating lobules
- Cytoarchitecture (within the lobules) consists of cells forming short chords, dense epithelioid sheets / nest and single cells within the matrix
- Extracellular myxoid matrix
- Physaliphorous cells
- Greek: Having bubbles or vacuoles
- Cells are epithelioid with abundant clear (glycogen) to eosinophilic cytoplasm that may be have a bubbly / vacuolated appearance
- Nuclear pleomorphism is heterogenous throughout the neoplasm, with low grade and higher grade areas; vesicular nucleus is common; nuclear pseudoinclusions may be seen
- Mitoses may be present
- Occasionally mitotically active spindle cells
- Chondroid chordoma:
- Matrix mimics hyaline cartilage (may be focal or extensive)
- De-differentiated chordoma:
- A biphasic tumor with two juxtaposed components:
- Chordoma, NOS component
- High grade sarcomatous component (high grade undifferentiated pleomorphic sarcoma or osteosarcoma)
Histological subtypes
Characteristic | Conventional chordoma | Chondroid chordoma | Dedifferentiated chordoma | Poorly differentiated chordoma, SMARCB1-deficient |
Percentage | 95% | 4% | <1% | ㅤ |
Age at diagnosis | Adults (96%) Median: 55 years | Adults (86%) Median: 45 years | Adults (96%) Median: 61 years | Children (86%) Median: 7 years |
M:F ratio | 1.7 | 1.1 | 1.8 | 0.7 |
Prior irradiation | No | No | Yes (25%) | No |
Localisation | Sacrococcygeal region (55%) | Skull base (73%) | Sacrococcygeal region (60%) | Skull base (64%) |
Histopathology | Classic | Chondroid | Conventional juxtaposed with sarcomatous (91%) Chondroid juxtaposed with sarcomatous (2%) Conventional chordoma transformed into pure sarcomatous tumour (7%) | Epithelioid No physaliphorous cells |
Histology | Divided into lobules by fibrous septa, with cells arranged in cords or ribbons within a myxoid matrix. | A subtype of the conventional form that contains an extracellular matrix mimicking hyaline cartilage. | Biphasic tumours where conventional chordoma is juxtaposed with high-grade sarcoma. | These are epithelioid and solid tumours with focal rhabdoid morphology; they lack physaliphorous cells |
Immunohistochemical profile | SMARCB1 (INI1) preserved Brachyury+ Pancytokeratin+ EMA+ S100+ | SMARCB1 (INI1) preserved Brachyury+ Pancytokeratin+ EMA+ S100+ | SMARCB1 (INI1) preserved Brachyury+/- ª Pancytokeratin- EMA- S100-/+ | Loss of SMARCB1 (INI1) Brachyury+ Pancytokeratin+ EMA+ S100+/- |
Outcome | Metastasis: 13% Local progression: 46% Median PFS: 24 months Death during follow-up: 29% Median OS: 48 months | Metastasis: 9% Local progression: 54% Median PFS: 26.5 months Death during follow-up: 42% Median OS: 43 months | Metastasis: 30% Local progression: 65% Median PFS: 6 months Death during follow-up: 61% Median OS: 15 months | Metastasis: 30% Local progression: 54% Median PFS: 4 months Death during follow-up: 43% Median OS: 13 months |
Immunophenotype
- +
- Cytokeratin
- EMA
- S100 protein
- Brachyury (a nuclear stain, highly specific)
- Decalcification may result in a loss / decrease in brachyury immunoreactivity
- Dedifferentiated component may lose brachyury, EMA or S100 protein
- -
- PTEN loss is common
- INI1 (aka SMARCB1) is occasionally lost
Aetiology
- Sporadic: most cases
- Familial:
- Tuberous sclerosis in children OR
- Children with Tuberous sclerosis have a higher incidence of Chordoma
- Familial cases with TBA7 gene (brachyury) duplication (6q27)
- TBA7 gene, which encodes the brachyury protein (a transcription factor critical for notochord development)
- T-box transcription factor involved in mesodermal differentiation during gastrulation (formation of 3 germ layers), including notochordal development
- Found in 7% of sporadic chordomas
- Familial associated tumors (autosomal dominant) are rare; they are associated with T gene duplication
Genetic profile
- Duplications of the TBA7 gene occur in 27% of cases
- Mutations in PIK3CA signalling occur in 7–10%.
- In poorly differentiated chordomas, loss of SMARCB1 protein results from a homozygous deletion of the SMARCB1 gene.
- LYST inactivating mutations are present in approximately 10% of cases.
Clinical presentation
- Average time from onset of symptoms to diagnosis averages 2 years.
- Due to compression of adjacent brainstem and cranial nerves (CN6) → neurological deficit
- Pain
Radiological
General
- Chordomas appear as lobular, lytic, and destructive midline lesions.
CT
- Centrally located
- Periphery
- Lytic bone tumor with osseous destruction and soft tissue invasion
- Well-circumscribed
- Within mass
- Expansile soft-tissue mass
- Usually hyper-attenuating relative to adjacent brain
- Inhomogenous areas may be seen due to necrosis or haemorrhage
- Soft-tissue mass is often disproportionately large relative to the bony destruction
- Irregular intratumoural calcifications (thought to represent sequestra of normal bone rather than dystrophic calcifications)
- Moderate to marked enhancement
MRI
- T1
- Intermediate to low-signal intensity
- Small foci of hyperintensity (intratumoural haemorrhage 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 tumour
- Greater enhancement has been associated with poorer prognosis
- SWI/GE:
- Variable intralesional haemorrhage, suggested by the presence of blooming artefact
- DWI/ADC
- Conventional chordoma: 1474 ± 117 x 10-6 mm2/s
- Dedifferentiated chordoma: 875 ± 100 x 10-6 mm2/s
Image
Management
- Work-up
- Staging is performed according to Union for International Cancer Control (UICC) bone sarcoma protocols.
- Surgery → radiation (proton beam)
- Gross total resection is challenging but important.
- Radical, complete, en-bloc resection without violation of the tumour has been shown to significantly reduce the rate of recurrence and improve survival
- High rate of recurrence following piecemeal resection
- Radiation alone in poor surgical candidates
- Although radiotherapy is an important therapeutic adjunct for cranial base chordomas, issues regarding both the timing of adjuvant radiotherapy, specifically after complete resection or only for residual/recurrent disease, and optimal type of radiotherapy are largely unresolved in the literature.
- Chordomas require a high dose for a radiobiologic response, which is unfortunate given their proximity to critical structures (e.g., optic and other cranial nerves, pituitary gland, and brain stem).
- As such, proton beam therapy has classically been considered to be well-suited for chordomas
- Other options (none have been shown to be superior)
- Fractionated radiotherapy, radiosurgery, and carbon-ion radiotherapy have all been used without any one modality showing superiority.
- Smaller volume tumours have been amenable to SRS, and early results have suggested comparable outcomes to other radiation modalities for residual or recurrent cases.
- Factors affecting the response rate of radiotherapy:
- Age
- Sex
- Tumour heterogeneity
- Extent of resection
- Among cases with subtotal resection, a residual tumor volume under 25-30 cm3 appears associated with better local control using adjunctive radiation therapy.
- Presence of necrosis in the pretreatment biopsy
- Elevated tumour volume
- Radiotherapy dose delivered.
- Poor response to chemotherapy
- Tyrosine kinase inhibitors have been used in advanced cases
Prognosis
- Median survival is 7 years
- Death due to local progression
- 5 year
- Overall survival: 61%
- Disease free survival: 71%
- 10 year
- Overall survival: 41%
- Disease free survival: 57%
- Outcomes vary significantly by histopathological type:
- Conventional chordoma: Median overall survival (OS) of 48 months; 13% metastasis rate.
- Chondroid chordoma: Median OS of 43 months; 9% metastasis rate.
- Dedifferentiated chordoma: Median OS of 15 months; 30% metastasis rate.
- Poorly differentiated chordoma: Median OS of 13 months; 30% metastasis rate.
- Metastasis
- 40% of non-cranial tumours metastasize (lung, bone, lymph nodes, subcutaneous tissue)
- Cranial chordomas: systemic metastasis 12.5%
- Negative prognostic factors for conventional chordoma include
- Age over 60 years,
- Skull base location,
- Worse prognosis in cranial cases as tendency to recur regardless of the treatment method chosen.
- Tumour size greater than 80 mm,
- Metastasis at diagnosis,
- Incomplete resection.
Differential diagnosis
- Chondrosarcoma:
- May be confused with chondroid chordoma but will be negative for epithelial markers (Cytokeratin / EMA) and brachyury;
- Unlike chordoma, chondrosarcoma may demonstrate IDH1 or IDH2 mutations
Features | Chordomas | Chondrosarcoma |
Location | Centre clival | Para-central petro-occipital fissure |
Origin | Notochordal | Mesenchymal |
Cells | Physaliphorous cells | Chondrocytes |
DWI MRI | Restricts more | Restricts less |
- Metastatic carcinoma: usually negative for S100 protein and brachyury
- Not usually lobulated with myxoid stroma
- Usually positive for "origin specific markers" (PAX8 in renal cell carcinoma, TTF1 in metastatic pulmonary adenocarcinoma, etc)
- Correlate with chest, abdomen and pelvic imaging
- Myxopapillary ependymoma:
- Involves the sacral region but negative for epithelial markers
- Craniopharyngiomas
- are said to arise from squamous cell rests from Rathke’s pouch, Chordomas are tumours of the notochord remnant cells.
- Ecchordosis physaliphora
- Gross image of skull base showing the optic chiasm (left center), basilar artery (left), and a focal gelatinous mass adjacent to the basilar artery.
- Such incidental notochordal rests (remnants) can be seen in 1-2% of autopsies usually located in the retroclival prepontine region, but can be found anywhere from the skull base to the sacrum.
- Ecchordosis physaliphora arise from remaining notochord cells along the axis of the spine after embryogenesis.
- Unfortunately, ecchordosis physaliphora and chordoma are histologically indistinguishable, other than by examining the margins, the later demonstrating infiltrative growth.
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