Neuro-Ophthalmic Manifestations of Chordoma
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Chordoma is a rare bone malignancy that is low-grade, highly recurrent, aggressive, and locally invasive. Chordomas can be located in the cranial, spinal, or sacral distributions. Patients with cranial chordoma may present with neuro-ophthalmic manifestations prior to diagnosis, including palsy of cranial nerve VI, most commonly, as well as that of cranial nerves III and VI. Common presenting symptoms include headache and diplopia, including intermittent diplopia.
Disease Entity
Chordoma is a rare, slow growing, locally invasive, and aggressive tumor that is derived from notochordal remnants.[1][2] Chordomas have a proclivity to develop in the axial skeleton, including the skull base, spine, and sacrum.[1][2] They are highly recurrent, have poor prognoses, and typically present late with non-specific symptoms and a large tumor burden, contributing to delayed diagnosis.[1][2] Skull-base chordomas may present with neuro-ophthalmic manifestations, including headache, diplopia, cranial nerve palsies, and occasionally visual field defects.[3][4][5]
Epidemiology
Chordomas account for 1-4% of all bone malignancies and have an incidence of 0.088 per 100, 000 people per year.[1][6] Although chordomas are histologically benign, they are highly recurrent and clinically aggressive, making their clinical course similar to more malignant clival, sacral, or spinal neoplasms.[1][6] Chordomas are midline and can be further characterized into the following subgroups from highest to lowest prevalence: cranial, sacral, and spinal. Prevalence rates are similar among the three distributions.[1][6] The median age of diagnosis is 58.5 years, and the incidence of chordomas increases with age, with the highest incidence among adults in the 75-84-year age group.[6][7] Individuals with chordomas in the skull base tend to be diagnosed at an earlier age compared to those with chordomas in the vertebrae.[8]
Etiology and Pathophysiology
Chordomas arise from remnants of the notochord that are undifferentiated and that persist in vertebral bodies and the axial skeleton, which is elucidated by evidence of notochord vestige locations mirroring the sites of chordoma development.[1] Because chordomas can be distributed either in the cranial, spinal, or sacral distributions, the site of the chordoma origins correlates with the clinical presentation.[1] Most chordomas occur sporadically; however, a rare subset of patients may have a genetic predisposition for chordoma.[9] One subset of familial chordoma involves the duplication of the T gene.[1] The T gene encodes for a transcription factor called brachyury, which is involved in the development of the notochord.[1] In fact, undifferentiated notochord in the embryonic axial skeleton expresses brachyury.[1] Although the linkage between excess brachyury and chordoma onset is yet to be elucidated, T gene duplication is one mechanism for familial chordoma.[1]
Risk Factors
Epidemiological analyses indicate that chordomas more commonly affect males.[8] In fact, among patients with skull-base chordomas, males tend to have higher risk of disease progression and mortality.[10] However, a systematic review of all chordomas revealed that female sex is an adverse prognostic factor for progression-free survival.[8] Other adverse risk factors for progression-free survival include older age, large tumor size or spread, subtotal resection, metastasis, recurrence, and differentiation on histological analysis.[8] There are no specific environmental risk factors for the onset of chordoma, and most individuals with chordoma lack a positive family history of chordoma, although a rare genetic predisposition may exist among individuals with familial chordoma, either with or without a germline duplication of the T gene.[9][11]
Diagnosis
History
A thorough history and review of systems should be identified, including ascertaining ocular and extraocular manifestations.[1] Due to the slow-growing nature of chordomas, symptoms tend to be vague and non-specific, thus contributing to late diagnoses.[1] The location of the chordoma (e.g., cranial, spinal, sacral) determine the symptoms that patients may experience. For instance, chordomas in the skull base may lead to cranial nerve palsies while spinal and sacral chordomas will lead to manifestations related to the corresponding spinal level of the chordoma.[1]
Physical examination
A complete neuro-ophthalmic exam should be considered and conducted among patients with chordoma and visual symptoms.[3][4][5]
Ocular Findings
In a study of 48 patients with skull-base chordoma, 52% of patients experienced ocular manifestations as the presenting symptom of the condition, including diplopia (54%), intermittent diplopia (25%), and reduced visual acuity (8%).[3] Additionally, 67% of patients experienced headaches, and 2% experienced facial numbness and weakness.[3] In terms of extraocular manifestations, 2% had reduced hearing or tinnitus, and 8% had dysphagia or dysarthria.[3] In addition, 46% experienced cranial nerve VI palsy, contributing to headache and diplopia.[3] More specifically, 29% had unilateral cranial nerve VI palsy alone, and 6% had bilateral cranial nerve VI palsy.[3] 6% had cranial nerve III palsy alone, and 2% had cranial nerve IV palsy alone.[3] Lastly, 2% of patients had skull-base chordoma that affected cranial nerves III, IV, and VI.[3]
Additionally, in a separate study of 63 patients with intracranial chordoma, 70% experienced diplopia, and 57% reported headache during the first visit.[4] Additionally, 16% experienced reduced visual acuity.[4] The presenting ocular symptoms were most commonly due to impact on cranial nerve VI.[4] More specifically, 29% experienced cranial nerve VI palsy as the isolated presenting manifestation, and 62% experienced palsies of extraocular muscles.[4] Regarding cranial nerve palsies, 56% of patients had cranial nerve VI palsies, 22% had cranial nerve III palsies, and 8% had cranial nerve IV palsies.[4] 24% of patients had left cranial nerve VI palsy alone, 10% had bilateral cranial nerve VI palsy, 5% had right cranial nerve VI palsy, 5% had left cranial nerves III and VI palsy, and 5% had cranial nerve III palsy alone.[4] Lastly, 3% of patients had intracranial chordoma that affected cranial nerves III, IV, and VI.[4] Regarding neuro-ophthalmic manifestations, 24% experienced visual field defects while 19% experienced optic atrophy or papilledema.[4] Furthermore, 6% and 5% of patients experienced facial numbness and weakness, respectively.[4] In terms of extraocular findings, 17% experienced ataxia, 11% experienced extremity weakness, 11% experienced dysphagia, and 6% experienced dysarthria.[4]
Skull-based chordomas commonly grow in the clivus, also known as clival chordoma, and subsequently present as cranial nerve palsies.[1] In the prior study of 63 patients with intracranial chordoma, 92% had clival chordoma, and the associated cranial nerve palsies depended on the direction of the tumor growth and spread.[4] Other case reports of neuro-ophthalmic manifestations of chordoma reveal vision loss from unilateral compressive optic neuropathy and isolated cranial nerve IV palsy secondary to clival chordoma.[12][13] Because chordomas grow slowly, they often present clinically only after entering the later stages.[1]
Laboratory test and Imaging
Diagnosis of chordoma relies on imaging and histopathology analyses.[1] MRI (T1-weighted or T2-weighted) or CT may be utilized to visualize any calcifications or bony characteristics; however, MRI or CT tend to not visualize beyond the S2 level.[1] Additionally, immunohistochemical markers in classic chordomas include S-100, epithelial membrane antigen (MUC1), cytokeratins, and possibly brachyury.[1]
During the complete neuro-ophthalmic exam, visual field testing (i.e., automated visual fields) should be obtained to identify potential signs of junctional scotoma or junctional scotoma of Traquair that correlate radiologically with mass effect.[3][4][5]
Differential diagnosis
When there is suspicion for chordoma, chondrosarcoma should also be on the differential due to the many similarities and difficulty in distinguishing between the two. Similar to chordomas, chondrosarcomas also have S-100 immunoreactivity and similar morphology, and they are also mesenchymal neoplasms.[1] In addition, skull-base chondrosarcoma manifests with similar symptoms prior to diagnosis as skull-base chordoma, including headache, diplopia, intermittent diplopia, reduced visual acuity, facial numbness and weakness, reduced hearing and tinnitus, dysphagia, and dysarthria.[3] Furthermore, among cranial neuropathies, cranial nerve VI palsies are most common among patients with either chordoma or chondrosarcoma.[3] However, chondrosarcomas tend to arise from the temporal bone while chordomas tend to emerge from the clivus.[3] Additionally, chondrosarcomas come from embryonal cartilage that persist and do not undergo endochondral ossification while chordomas originate from notochordal remnants.[3] Lastly, chordomas tend to be midline, which is not always the case for chondrosarcomas.[3]
Management
General treatment
The major treatment avenues include either surgical resection or radiation therapy.[1] When possible, resection is performed.[1] However, en-bloc resection of chordomas can be done in only about half of sacral chordomas and lower percentages of spinal and skull-based chordomas.[1] This contributes to the high rate of recurrence. [1]After surgical resection or if surgical resection is not possible, radiation therapy is utilized.[1] The combination of surgical removal and radiation therapy provide greater benefit together.[1] Due to the high recurrence rate, repeated radiation therapy or surgical resection may be needed; however, the risk of radiation toxicity and the risk of reoperation need to be taken into account.[1] Although chordomas are not typically sensitive to chemotherapy, active research aims to identify the role of targeted immunotherapy based on the gene mutations of specific chordomas (i.e., PDGFR, EGFR).[1][14]
Prognosis
Due to its high recurrence, aggressive nature, and locally invasiveness, chordomas tend to have poor prognoses.[1] Chordomas have a median survival of 6.29 years.[1][7] Survival rates decrease with time; the 5-year survival rate is 67.6%, 10-year survival rate is 39.9%, and 20-year survival rate is 13.1%.[1][7] Additionally, compared to just surgical resection alone, surgical resection with positive margins and radiation therapy together enhances the 5-year survival rate from 71% to 82%.[15]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 1.24 1.25 1.26 1.27 1.28 1.29 1.30 1.31 Walcott BP, Nahed BV, Mohyeldin A, Coumans J-V, Kahle KT, Ferreira MJ. Chordoma: current concepts, management, and future directions. The Lancet Oncology. 2012;13(2):e69-e76.
- ↑ 2.0 2.1 2.2 Barber SM, Sadrameli SS, Lee JJ, et al. Chordoma—Current Understanding and Modern Treatment Paradigms. Journal of Clinical Medicine. 2021;10(5):1054.
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 Volpe NJ, Liebsch NJ, Munzenrider JE, Lesseil S. Neuro-ophthalmologic Findings in Chordoma and Chondrosarcoma of the Skull Base. American Journal of Ophthalmology. 1993;115(1):97-104.
- ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 Bagan SM, Hollenhorst RW. Ocular manifestations of intracranial chordomas. Trans Am Ophthalmol Soc. 1980;78:148-155.
- ↑ 5.0 5.1 5.2 Sampige RR, Nguyen TA, Alryalat SA, Al Deyabat O, Lee AG. Nasal Hemianopic Junctional Scotoma of Traquair Secondary to Chordoma. Journal of Neuro-Ophthalmology. 2024:1-3.
- ↑ 6.0 6.1 6.2 6.3 Das P, Soni P, Jones J, et al. Descriptive epidemiology of chordomas in the United States. Journal of Neuro-Oncology. 2020;148(1):173-178.
- ↑ 7.0 7.1 7.2 McMaster ML, Goldstein AM, Bromley CM, Ishibe N, Parry DM. Chordoma: incidence and survival patterns in the United States, 1973–1995. Cancer Causes & Control. 2001;12(1):1-11.
- ↑ 8.0 8.1 8.2 8.3 Bakker SH, Jacobs WCH, Pondaag W, et al. Chordoma: a systematic review of the epidemiology and clinical prognostic factors predicting progression-free and overall survival. European Spine Journal. 2018;27(12):3043-3058.
- ↑ 9.0 9.1 Parry DM, McMaster ML, Liebsch NJ, et al. Clinical findings in families with chordoma with and without T gene duplications and in patients with sporadic chordoma reported to the Surveillance, Epidemiology, and End Results program. J Neurosurg. 2021;134(5):1399-1408.
- ↑ Rachinger W, Eigenbrod S, Dützmann S, et al. Male sex as a risk factor for the clinical course of skull base chordomas: Clinical article. Journal of Neurosurgery. 2014;120(6):1313-1320.
- ↑ Chordoma Study. National Cancer Institue: Division of Cancer Epidemiology and Genetics. Accessed 2024. https://dceg.cancer.gov/research/clinical-studies/chordoma.
- ↑ Pellegrini F, Brocca D, Cuna A, Stafa A, Lee AG. Unilateral Compressive Optic Neuropathy As the Presenting Manifestation of Clival Chordoma: A Case Report. Cureus. 2022;14(4):e24440.
- ↑ Hall MN, Raviskanthan S, Mortensen PW, Lee AG. Isolated Fourth Nerve Palsy as the Presenting Sign of Clival Chordoma. Journal of Neuro-Ophthalmology. 2022;42(1):e391-e393.
- ↑ Yang X, Li P, Kang Z, Li W. Targeted therapy, immunotherapy, and chemotherapy for chordoma. Current Medicine. 2023;2(1):1-6.
- ↑ Dial BL, Kerr DL, Lazarides AL, et al. The Role of Radiotherapy for Chordoma Patients Managed With Surgery: Analysis of the National Cancer Database. Spine. 2020;45(12):E742-e751.
