Chordoma

Chordoma is a malignant tumor arising from embryonic notochord remnants, accounting for 50% at the sacrum, 35% at the skull base/clivus, and 15% in the mobile spine (cervical most common). Histologically, physaliferous cells (vacuolated, bubbly cytoplasm) are pathognomonic, and brachyury is a specific nuclear immunohistochemical marker (T-box transcription factor); tumors are also S100+ and cytokeratin+. Chordoma is slow-growing but locally aggressive with high recurrence rates—wide surgical resection with clear margins is the only chance for cure, as intralesional margins result in 50-90% local recurrence. Proton beam radiotherapy is used for unresectable tumors or as adjuvant therapy. Conventional chemotherapy has limited efficacy. Ten-year survival is approximately 40-60%.

Chordoma is a rare, slow-growing but locally aggressive malignant bone tumor arising from remnants of the embryonic notochord. It represents approximately 1-4% of all primary malignant bone tumors and accounts for approximately 20% of primary spine tumors.

Definition

Chordoma is a primary malignant bone tumor originating from notochordal remnants. Despite being classified as a low-grade malignancy based on histologic appearance, chordomas demonstrate locally aggressive behavior with high rates of local recurrence and potential for distant metastasis.

Epidemiology

Incidence: Rare tumor with annual incidence of approximately 0.08 per 100,000 population. Approximately 300 new cases diagnosed annually in the United States.

Age distribution: Typically presents in adults with peak incidence in the 5th to 7th decades (50-70 years). Can occur in children (approximately 5% of cases), where skull base location is more common.

Sex predilection: Male predominance with male-to-female ratio of approximately 2:1.

Location distribution:

• Sacrum: 50% (most common site)
• Skull base (clivus): 35% (second most common)
• Mobile spine: 15% (cervical greater than thoracic greater than lumbar)

The exclusive location in the axial skeleton reflects the embryologic distribution of notochord remnants.

Pathogenesis

The notochord is a transient embryonic structure that appears during the third week of gestation and serves as the primitive axial skeleton. It induces formation of the vertebral column and skull base, then normally undergoes complete regression by 8 weeks of gestation. The only normal remnant is the nucleus pulposus of intervertebral discs.

Chordoma arises from ectopic notochordal cell rests that persist after embryogenesis. These remnants are found in the axial skeleton, explaining why chordoma occurs exclusively in midline structures (sacrum, clivus, vertebrae). The tumor demonstrates notochordal differentiation with expression of brachyury, a T-box transcription factor essential for notochord development.

Genetics: Familial chordoma is rare but described. Duplications of the brachyury gene (TBXT) on chromosome 6q27 are associated with familial chordoma. Most cases are sporadic without identified hereditary pattern.

Molecular Biology

Brachyury expression: The defining molecular feature of chordoma is expression of brachyury (encoded by TBXT gene), a T-box transcription factor critical for notochord development. Brachyury is expressed in over 95% of chordomas and is considered pathognomonic. It is not expressed in morphologic mimics such as chondrosarcoma.

Genetic alterations: Chordomas demonstrate relatively simple karyotypes compared to other sarcomas. Common alterations include:

• Loss of chromosome 1p (associated with worse prognosis)
• Loss of 9p (CDKN2A/p16 locus)
• Amplification or mutation of EGFR and PDGFR pathways
• TP53 mutations in some cases

Growth characteristics: Despite low mitotic rate and bland cytologic features, chordomas are locally aggressive. They demonstrate:

• Slow but persistent growth
• Local invasion of bone and soft tissue
• Entrapment of neurovascular structures
• High local recurrence rates (30-50% even with adequate resection)
• Late distant metastasis potential (10-40%, usually to lungs, bone, liver)

Histological Subtypes

Conventional (classic) chordoma: 80% of cases. Lobulated architecture with cords and sheets of tumor cells in abundant myxoid matrix. Characteristic physaliferous cells (physaliphorous = bubble-bearing) are large cells with vacuolated, bubbly cytoplasm containing glycogen and mucin. Nuclei are typically small, round, and bland. Mitotic figures are rare.

Chondroid chordoma: 5-15% of cases. Contains areas of hyaline cartilage in addition to typical chordoma features. More common in skull base. Historically considered to have better prognosis, though recent studies suggest similar outcomes to conventional type when adequately treated. Must distinguish from chondrosarcoma using brachyury immunostaining.

Dedifferentiated chordoma: Less than 5% of cases. Contains areas of high-grade sarcomatous transformation with increased cellularity, atypia, and mitotic activity. Worst prognosis with more aggressive behavior and higher metastatic potential. Can occur de novo or in recurrent tumors. Median survival approximately 1 year.

Poorly differentiated chordoma: Rare variant seen primarily in children and young adults. Lacks typical physaliferous cells. More aggressive clinical course.

Sacral Chordoma

Presents with nonspecific symptoms leading to delayed diagnosis. Average symptom duration before diagnosis is 6-12 months.

Pain: Most common presenting symptom (70-80% of patients). Initially mild, intermittent sacral or coccygeal pain. Progressively worsens and becomes constant. May radiate to buttocks, hips, or lower extremities.

Neurological symptoms: Occur in approximately 50% at presentation. Include:

• Radicular pain (L5, S1 dermatomes most common)
• Motor weakness (foot drop from L5 involvement)
• Sensory changes in saddle distribution
• Bowel dysfunction (constipation most common)
• Bladder dysfunction (urinary retention or incontinence)
• Sexual dysfunction

Pelvic mass: Large tumors may cause palpable presacral mass on rectal examination. Anterior extension can cause:

• Constipation or change in bowel habits
• Urinary symptoms from bladder compression
• Dyspareunia in women
• Rectal bleeding (rare, suggests mucosal invasion)

Skull Base Chordoma

Presents earlier due to critical location.

Cranial nerve palsies: Most common presentation (60-70%). Abducens nerve (CN VI) most commonly affected, causing diplopia. Other cranial nerves can be involved depending on extension.

Headache: Present in 40-50% of patients. Typically retro-orbital or vertex headache.

Visual symptoms: Diplopia, visual field defects, decreased visual acuity.

Endocrine dysfunction: Large tumors can affect pituitary function causing hypopituitarism.

Nasal/pharyngeal symptoms: Nasal obstruction, epistaxis, dysphagia with anterior extension.

Mobile Spine Chordoma

Neck or back pain: Localized pain at tumor site. Initially mechanical, progressively worsens.

Radiculopathy: Nerve root compression causes dermatomal pain and neurological deficits.

Myelopathy: Spinal cord compression causes:

• Upper motor neuron signs below level of lesion
• Gait disturbance
• Bladder and bowel dysfunction
• Sensory level

Physical Examination

Inspection: May reveal visible/palpable mass in advanced cases.

Neurological examination:

• Comprehensive motor examination (look for lower motor neuron signs from nerve root involvement)
• Sensory testing (dermatomes, saddle anesthesia)
• Reflexes (may be diminished with nerve root compression)
• Rectal tone assessment
• Perianal sensation

Rectal examination: Essential for sacral lesions. May palpate presacral mass - typically firm, fixed, smooth or lobulated.

Laboratory Studies

Routine labs: Generally normal. CBC, basic metabolic panel to assess baseline function.

Tumor markers: No specific serum markers for chordoma. Alkaline phosphatase may be elevated but is nonspecific.

Imaging

Tissue Diagnosis

Biopsy indications: Tissue diagnosis mandatory before definitive treatment. Clinical and imaging features alone cannot definitively diagnose chordoma.

Biopsy technique: Image-guided core needle biopsy preferred (CT or fluoroscopy guidance). Considerations:

• Plan biopsy tract to allow en bloc excision with definitive surgery
• Avoid contaminating uninvolved tissue planes
• Obtain adequate tissue for histology and immunohistochemistry
• Posterior approach typically used for sacral lesions
• Send fresh tissue if molecular studies planned

Open biopsy: Reserved for cases where core biopsy nondiagnostic or inadequate. Risks tumor contamination of surgical field.

Staging Investigations

Chest imaging: Chest CT required to exclude pulmonary metastases.

Whole spine imaging: MRI of entire spine to assess for skip metastases (rare but described).

Skeletal survey or bone scan: Consider if symptoms suggest other skeletal involvement.

Laboratory: Baseline renal and hepatic function for treatment planning.

Gross Pathology

Lobulated, gelatinous gray-white to tan mass. Cut surface demonstrates mucoid, glistening appearance. Hemorrhage and necrosis uncommon except in dedifferentiated variants. Soft tissue component often extensive.

Microscopic Features

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Architecture: Lobular growth pattern separated by fibrous septae. Cords, nests, and sheets of tumor cells in abundant extracellular myxoid matrix.

Cytology:

• Physaliferous cells: Pathognomonic feature. Large cells with abundant, vacuolated, bubbly cytoplasm (vacuoles contain mucin and glycogen). Cytoplasmic vacuoles push nucleus to periphery creating signet-ring appearance in some cells.
• Nuclei: Small, round to oval, centrally or eccentrically placed. Minimal pleomorphism in conventional type.
• Mitotic activity: Rare mitotic figures (fewer than 1 per 10 high-power fields in conventional type).

Matrix: Abundant extracellular myxoid/mucoid matrix rich in proteoglycans. Matrix stains with Alcian blue (blue) and mucicarmine (pink).

Immunohistochemistry

Brachyury (T-brachyury): DIAGNOSTIC MARKER. Nuclear expression in over 95% of chordomas. Highly specific - positive only in chordoma and normal notochord. Negative in chondrosarcoma and other mimics. This is the single most important immunostain to confirm diagnosis.

S100 protein: Positive in 80-100% of cases. Strong, diffuse nuclear and cytoplasmic staining. Also positive in chondrosarcoma (thus not specific).

Cytokeratin: Positive in 80-100%. Includes low molecular weight keratins (CAM 5.2, AE1/AE3). Dot-like paranuclear pattern characteristic.

EMA (epithelial membrane antigen): Positive in most cases (70-90%).

Vimentin: Variably positive.

NEGATIVE stains: Desmin, smooth muscle actin, chromogranin, synaptophysin (helps exclude other tumor types).

Differential Diagnosis

Chondrosarcoma: Most important differential, especially for chondroid chordoma. Both can have cartilaginous matrix and S100 positivity. Brachyury distinguishes: positive in chordoma, negative in chondrosarcoma. Cytokeratin also typically negative in chondrosarcoma.

Metastatic carcinoma: Axial skeleton location and cytokeratin positivity can mimic metastatic adenocarcinoma. Brachyury negative in carcinomas. Clinical history and additional immunostains help.

Myxopapillary ependymoma: Occurs in sacrococcygeal region, can have myxoid matrix. Lacks physaliferous cells and brachyury positivity. GFAP positive (negative in chordoma).

Ecchordosis physaliphora: Benign notochordal remnant typically found incidentally at clivus. Small (less than 2 cm), no bone destruction, identical histology to chordoma. Clinical and imaging features distinguish.

Conventional Photon Radiation

Chordomas are relatively radioresistant to conventional photon radiation. Doses required for control (greater than 70 Gy) exceed tolerance of surrounding normal tissues (brainstem, spinal cord, bowel, bladder). Therefore, conventional radiation has limited efficacy as primary treatment but may be used in palliative settings.

Proton Beam Therapy

Mechanism: Protons deposit maximum energy at a specific depth (Bragg peak) with minimal exit dose. This allows delivery of high radiation doses to tumor while sparing adjacent normal tissues.

Indications:

• Unresectable chordomas (skull base, sacral with major vascular involvement)
• Positive margins after surgery (adjuvant)
• Recurrent tumors not amenable to further surgery
• Patient choice when surgery declined

Dosing: Typical doses 70-80 Gy (RBE) in 35-40 fractions.

Outcomes:

• 5-year local control: 60-80% for skull base chordomas
• 5-year local control: 50-70% for sacral chordomas
• Best results when combined with maximal safe surgery

Availability: Limited to specialized centers with proton beam facilities.

Carbon Ion Therapy

Similar concept to proton therapy but with theoretical radiobiologic advantages. Available at even fewer centers worldwide. Emerging evidence suggests similar or slightly better local control compared to proton therapy.

Conventional Radiation Role

Palliative treatment: Pain control, symptom management in metastatic disease or patients not candidates for surgery/proton therapy.

Adjuvant after intralesional surgery: May reduce recurrence risk but inferior to proton therapy.

Chemotherapy

Conventional cytotoxic chemotherapy has no established role in chordoma management. Chordomas are not chemosensitive. Multiple agents tested in clinical trials (ifosfamide, doxorubicin, cisplatin, temozolomide) with minimal response rates.

Targeted Therapies

Based on molecular profiling showing activation of receptor tyrosine kinase pathways, several targeted agents have been investigated:

Imatinib: PDGFR inhibitor. Small series showed disease stabilization in some patients but no objective responses. May have role in metastatic/unresectable disease.

EGFR inhibitors (erlotinib, cetuximab): Occasional responses reported in case reports. No large trials.

mTOR inhibitors: Under investigation based on pathway activation in some chordomas.

Immunotherapy: Checkpoint inhibitors being explored. Response rates appear low given low mutational burden of chordomas. Brachyury-targeted vaccine in clinical trials.

Current Approach to Systemic Therapy

No standard systemic therapy exists. For patients with metastatic or unresectable progressive disease, consider:

• Clinical trial enrollment (preferred)
• Targeted therapy (imatinib or EGFR inhibitor) with understanding of limited evidence
• Palliative care focus

Surgical Complications

Intraoperative:

• Hemorrhage: Sacral resections can involve significant blood loss (presacral venous plexus, iliac vessels). Blood transfusion commonly required.
• Dural tear: High risk in spine cases. CSF leak risk.
• Vascular injury: Iliac vessels at risk in sacral surgery. Requires vascular surgery availability.
• Nerve injury: Intentional sacrifice versus inadvertent injury to roots intended to preserve.

Early postoperative:

• Wound complications: Infection, dehiscence, seroma. High rate (20-40%) given large dead space and possible contamination.
• Deep infection: Potential for infection of hardware/reconstruction. May require removal and prolonged antibiotics.
• Neurologic deficits: Lower extremity weakness, bladder/bowel dysfunction if nerve roots sacrificed or injured.
• Venous thromboembolism: High risk due to pelvic surgery and immobility.

Late complications:

• Chronic pain: Neuropathic pain common, especially with nerve root sacrifice.
• Bladder dysfunction: Requires intermittent catheterization or indwelling catheter if bilateral S2 sacrifice.
• Bowel dysfunction: Constipation most common. May require bowel regimen or colostomy if severe.
• Sexual dysfunction: Erectile dysfunction in men, dyspareunia in women.
• Implant failure: Spinopelvic fixation failure can occur (5-10% of cases).
• Sacral insufficiency: Stress fractures of remaining sacrum.

Radiation Complications

Acute: Skin erythema, mucositis (skull base), diarrhea (sacral).

Late:

• Radiation necrosis: Brain/brainstem necrosis (skull base tumors), bowel injury (sacral tumors)
• Secondary malignancy: Long-term risk of radiation-induced sarcoma
• Endocrine dysfunction: Hypopituitarism after skull base radiation
• Neurologic deficits: Cranial neuropathies, myelopathy risk

Proton/carbon ion therapy reduces risk of late complications compared to conventional radiation due to normal tissue sparing.

Disease-Related Complications

Local progression: Pain, neurologic deterioration, mass effect on pelvic organs.

Metastatic disease: Occurs in 10-40% of patients, usually late in disease course. Lungs most common site, followed by bone and liver. Median time to metastasis is 5-7 years after diagnosis.

Prognostic Factors

Margin status: Single most important factor. Wide negative margins associated with significantly better local control and survival.

• Wide margins: 5-year local recurrence 10-30%
• Marginal/intralesional: 5-year local recurrence 50-90%

Tumor location:

• Sacral: Generally better prognosis (more amenable to wide resection)
• Skull base: More challenging to achieve margins, often require adjuvant radiation
• Mobile spine: Intermediate prognosis

Histologic subtype:

• Conventional: Standard prognosis
• Chondroid: Similar to conventional when adequately treated
• Dedifferentiated: Worst prognosis (median survival approximately 1 year)

Tumor size: Larger tumors associated with worse outcomes (harder to achieve margins, more likely to involve critical structures).

Age: Younger age generally associated with better survival.

Recurrence status: Recurrent tumors have worse prognosis than primary tumors.

Survival Data

5-year overall survival: 65-80% 10-year overall survival: 40-60% 5-year progression-free survival: 50-70% with optimal treatment

Cause of death: Most patients who die of chordoma do so from local progression rather than distant metastases. Uncontrolled local disease in sacrum or skull base causes significant morbidity.

Surveillance Protocol

Imaging schedule:

• Years 1-2: MRI of primary site every 3-4 months
• Years 3-5: MRI every 6 months
• After 5 years: Annual MRI
• Chest CT: Annually to monitor for pulmonary metastases
• Whole body imaging: Consider if symptoms suggest new disease sites

Clinical follow-up: Assess for symptoms of local recurrence, neurologic function, pain control, functional status (bowel/bladder).

Long-term surveillance: Lifelong follow-up recommended as late recurrences occur (can recur 10-20 years after initial treatment).

• Proton versus carbon ion therapy: Both spare normal tissue via the Bragg peak, but no randomised trial compares them. Carbon ions carry a higher relative biological effectiveness and may suit radioresistant tumours, yet are available at very few centres. Choice is largely driven by access rather than proven superiority.

• Definitive radiotherapy versus mutilating surgery: For high sacral or skull-base tumours where wide resection would cost bladder, bowel and ambulatory function, the threshold for offering definitive high-dose particle therapy instead of en bloc resection remains a genuine MDT judgement, not a settled algorithm.

• Prognostic weight of the chondroid variant: Historically considered favourable, but several modern series suggest outcomes equal to conventional chordoma once margin and dose are controlled for. The variant is now seen more as a histological than a prognostic distinction.

• Role of systemic therapy: Imatinib gives disease stabilisation (clinical benefit ~64%) but almost no objective shrinkage (ORR 2% in the phase II trial). EGFR inhibitors, brachyury-targeted vaccines and immune checkpoint blockade remain investigational; none is standard of care.

• Optimal surveillance duration: Late recurrences and metastases (well beyond 10 years) mean the ideal length and intensity of lifelong imaging follow-up is not evidence-defined and varies between centres.

Global Epidemiology

Chordoma is uniformly rare worldwide, with a population-based incidence of approximately 0.08 per 100,000 (SEER, McMaster 2001). There is a consistent male predominance (~1.7:1) and a peak in the fifth to seventh decades, with cranial disease over-represented in younger patients and children. Population (SEER) data show a roughly even axial distribution (cranial ~32%, mobile spine ~33%, sacrum ~29%), whereas surgical series quote the classic sacrum 50% / skull base 35% / mobile spine 15% because surgically resected sacral tumours are over-represented.

Side-by-Side Guideline Comparison

The unifying message across all bodies is identical: wide en bloc resection at a high-volume reference centre, with high-dose particle radiotherapy reserved for inadequate margins or unresectable disease, and no role for routine cytotoxic chemotherapy.

Registry and Reference-Centre Notes

• Chordoma is too rare for arthroplasty-style implant registries; the most robust outcome data come from national sarcoma databases and reference-centre series (e.g. Rizzoli, MD Anderson, Massachusetts General, Swedish Musculoskeletal Tumour Centre).
• The Chordoma Foundation maintains an international patient registry and biobank that increasingly drives multi-centre collaborative evidence.

High- vs Limited-Resource Practice Variation

• Particle therapy (proton/carbon ion) is concentrated in a small number of centres in North America, Europe and East Asia; many regions require interstate or international referral, creating access inequity and treatment delay.
• In limited-resource settings, conventional photon radiotherapy and the quality of the index surgical resection carry disproportionate weight, since a contaminated first operation cannot be undone and dominates lifelong local-control prospects.
• Early referral before biopsy to a specialist tumour centre is the single most transferable, resource-independent quality measure, ensuring a correctly planned, excisable biopsy tract.