Chordoma is a rare, low-grade malignant bone tumor arising from remnants of the notochord. It was first described by Rudolf Virchow in 1857 as a tumor of the clivus2).
It accounts for 1–4% of all primary malignant bone tumors, with an estimated annual incidence of 0.088 per 100,000 people. Incidence varies by country and ethnicity, ranging from 0.18 to 0.84 per million per year3). The median age at diagnosis is 58.5 years, with the highest frequency in the 75–84 age group.
The distribution of occurrence is: sacrum 50%, skull base 30%, and spine 20%4). Skull base chordomas tend to be diagnosed at a younger age than vertebral chordomas, and 92% of skull base chordomas arise in the clivus. Clival chordomas extend toward the cavernous sinus and superior orbital fissure, causing cranial nerve palsies, particularly abducens nerve palsy, leading to neuro-ophthalmologic symptoms.
Histological classification according to WHO includes four types: conventional (about 95%), chondroid (5–15%), dedifferentiated, and poorly differentiated2).
Median survival is 6.29–7.7 years3), with 5-year survival of 50–70%, 10-year survival of about 40%, and 20-year survival of 13.1%, indicating poor long-term prognosis.
Key epidemiological data are summarized below.
| Indicator | Value |
|---|---|
| Proportion of all malignant bone tumors | 1–4% |
| Annual incidence rate | 0.088 per 100,000 people |
| Median age at diagnosis | 58.5 years |
| 5-year survival rate | 50–70% |
| 10-year survival rate | Approximately 40% |
| Median survival time | 6.29–7.7 years |
It accounts for 1–4% of all malignant bone tumors, with an estimated annual incidence of 0.088 per 100,000 people. The median survival time is 6.29–7.7 years 3), and long-term follow-up is required.
The subjective symptoms of skull base chordoma vary depending on the type of cranial nerve compressed by the tumor and the direction of growth.
Abducens nerve (cranial nerve VI) palsy is the most common clinical finding. The abducens nerve emerges from the pons, ascends along the clivus for a long distance, passes through the petrosphenoidal ligament, enters the cavernous sinus, and reaches the lateral rectus muscle via the superior orbital fissure. Because of this long ascending course along the clivus, it is anatomically susceptible to compression by clival tumors. Tumors account for approximately 26% of causes of abducens nerve palsy.
Abducens Nerve (VI) Palsy
Most frequent cranial nerve palsy: Observed in 46% (unilateral 29%, bilateral 6%) of a 48-case study and 56% of a 63-case study.
Clinical findings: Abduction deficit on the affected side, esotropia, horizontal diplopia.
Breakdown of a 63-case study: Isolated left abducens nerve palsy 24%, bilateral abducens nerve palsy 10%, right abducens nerve palsy 5%.
Oculomotor and Trochlear Nerve (III, IV) Palsy
Oculomotor nerve (III) palsy: 6% in a 48-case study, 22% in a 63-case study. Presents with ptosis, mydriasis, and impaired eye movement.
Trochlear nerve (IV) palsy: 2% in a 48-case study, 8% in a 63-case study. Characterized by vertical diplopia and head tilt.
Combined III, IV, and VI palsy: 2–3%. Corresponds to orbital apex syndrome or cavernous sinus syndrome, presenting with total ophthalmoplegia combined with trigeminal nerve first branch and optic nerve involvement.
Other neuro-ophthalmologic findings include the following.
Diagnosis of abducens nerve palsy is based on confirmation of esotropia and limitation of abduction (cover test, Hess chart). Head CT or MRI is used to search for lesions in the brainstem, skull base, cavernous sinus, and orbital region.
Diplopia is the most common initial symptom (54–70%), and abducens nerve palsy is the most common clinical finding (46–56%). Due to the anatomical course of the abducens nerve ascending along the clivus, it is susceptible to compression by clival chordoma, resulting in esotropia and horizontal diplopia.
Chordomas arise from undifferentiated notochordal cells (notochordal remnants) that persist in the vertebral bodies or axial skeleton.
Imaging evaluation with head CT and MRI is fundamental.
Biopsy is necessary for definitive diagnosis.
Differentiation between chordoma and chondrosarcoma is particularly important. They are distinguished by site of origin and immunohistochemical profile.
| Feature | Chordoma | Chondrosarcoma |
|---|---|---|
| Site of origin | Midline (clivus) | Temporal bone origin |
| brachyury | Positive | Negative |
| S-100 | Positive | Positive |
Other differential diagnoses include the following:
Immunohistochemically, brachyury positivity is specific to chordoma and is the most important distinguishing point from chondrosarcoma 2). Additionally, chordoma arises in the midline (clivus), whereas chondrosarcoma often originates from the temporal bone. Note that both show S-100 positivity.
Surgical resection is the mainstay of treatment.
Used after surgical resection or for unresectable cases.
Chordoma is a chemotherapy-resistant tumor, usually with low sensitivity. In a Phase II trial, nitrocamptothecin showed response in only 1 of 15 cases 1). Main treatment is a combination of surgical resection and radiation therapy.
Treatment of the underlying chordoma is the priority, but if palsy persists, the following ophthalmic symptomatic treatments are performed.
Chordoma is a chemotherapy-resistant tumor, and its sensitivity to conventional chemotherapy is low 1). Standard treatment is a combination of surgical resection and radiation therapy (including proton beam therapy). For investigational molecular targeted drugs, see the section on latest research and future prospects.
Chordoma arises from notochordal remnants. Notochordal cells have large intracellular vacuoles and are surrounded by a notochordal sheath rich in collagen, laminin, and proteoglycans 2).
Characteristics by histological type are as follows.
The immunohistochemical profile shows positivity for brachyury, cytokeratin, EMA, and S-100. After radiation therapy, loss of S-100 and brachyury expression may occur 2).
Brachyury (T gene product) is a transcription factor involved in notochord development. Duplication of the T gene is one mechanism of familial chordoma, and overexpression is also observed in sporadic cases.
Overexpression of brachyury promotes epithelial-mesenchymal transition (EMT), enhancing tumor cell motility, invasiveness, and drug resistance 2). Concurrent loss of PTEN and CDKN2A (p16) is associated with elevated Ki-67, increased risk of metastasis, and shortened survival 2).
As a clival chordoma grows, it extends toward the cavernous sinus and superior orbital fissure, compressing cranial nerves. The abducens nerve originates from the nucleus in the pons (protruding into the floor of the fourth ventricle), ascends along the sphenoid clivus, passes under the petrosphenoid ligament, runs through the lateral wall of the cavernous sinus, traverses the superior orbital fissure, and reaches the lateral rectus muscle. This long ascending clival course is anatomically vulnerable to compression by clival tumors, explaining why abducens nerve palsy is the most common cranial nerve deficit.
When the tumor compresses the optic nerve, it causes papilledema, pallor, relative afferent pupillary defect (RAPD), decreased visual acuity, and visual field defects. Bilateral papilledema due to increased intracranial pressure may also be observed.
No molecular targeted drugs have been approved at present 1). The following are treatment options under research or in use.
Apps J, et al. (2023) reported that imatinib (PDGFR inhibitor) was used in over 200 cases but had low response rates, possibly related to PDGFR expression 1). The combination of imatinib + everolimus in 43 patients with progressive chordoma showed a response rate of 20.9% (Choi criteria), suggesting involvement of mTOR pathway activation 1).
Silva Junior LFM, et al. (2025) reported a case of a 35-year-old woman with clival chordoma that shrank by 98.9% after COVID-19 infection 3). They confirmed the presence of tumor-infiltrating T cells (CD3+) and macrophages (CD68+) and the absence of NK cells (CD56), suggesting the possibility of an antitumor immune response mediated by cross-reactive T cell activation due to SARS-CoV-2 3). Four previous cases of spontaneous regression (complete regression after E. coli infection, 33% shrinkage after M. marinum infection, etc.) have also been reported 3).
Apps J, et al. (2023) reported the 13-year course of an infant with giant clival chordoma complicated by tuberous sclerosis 1). Despite treatment with imatinib + sirolimus, everolimus, ifosfamide/doxorubicin, carboplatin/etoposide-containing regimens, surgical resection, and 54 Gy photon radiotherapy, the patient died at 13 years and 3 months of age. This case is reported as demonstrating the limited efficacy of molecular targeted therapy and chemotherapy in pediatric chordoma 1).
