Chordoma: Symptoms, Types, Causes and Treatment

Chordoma is a rare, malignant bone cancer that arises from remnants of the notochord, an embryonic structure crucial to spine development. Although it grows slowly, chordoma is locally aggressive and can lead to significant health challenges due to its proximity to the spinal cord and brain. Understanding its symptoms, types, causes, and available treatments is essential for both patients and caregivers navigating this complex disease. In this article, we’ll provide a detailed, evidence-based overview, synthesizing the latest research and clinical insights.

Symptoms of Chordoma

Chordoma may be rare, but its symptoms can have a profound impact on a person’s quality of life. Because these tumors grow along the spine and skull base, symptoms often depend on the tumor’s location and size. Early signs are frequently subtle, leading to delayed diagnosis—a source of frustration and anxiety for many patients and their families. Recognizing the hallmark symptoms can facilitate earlier intervention and better outcomes.

Symptom	Description	Frequency/Location	Source(s)
Pain	Persistent, often chronic, localized	Back, neck, sacrum	1 2 5 7
Neurological	Weakness, numbness, nerve impairment	Arms, legs, cranial nerves	1 2 3 5
Visual	Double vision, vision loss, headaches	Skull base tumors	3 5
Mass/Lump	Palpable swelling or lump	Sacrum, coccyx	5
Bowel/Bladder	Incontinence or dysfunction	Lower spine, sacrum	5
Fatigue	Persistent exhaustion	General	2
Emotional	Depression, anxiety	General	2

Table 1: Key Symptoms of Chordoma

Understanding Chordoma's Symptom Profile

Chordoma’s symptom spectrum is shaped by its location along the axial skeleton.

Pain and Physical Symptoms

• Chronic localized pain is the most commonly reported symptom, often affecting the lower back, tailbone (sacrum), or neck. This pain tends to be persistent, gradually worsening over time as the tumor grows and invades nearby tissue 1 2 5 7.
• Palpable mass or swelling: In sacrococcygeal chordomas, the tumor may grow large enough to be felt through the skin, sometimes presenting as a visible or palpable lump near the tailbone 5.

Neurological and Functional Impairments

• Nerve involvement: As chordomas compress or invade nerves, patients may experience weakness, numbness, or tingling in the arms or legs. If the tumor is at the base of the skull, symptoms can include cranial nerve dysfunction, such as difficulty swallowing, facial numbness, or hoarseness 1 3 5.
• Bowel and bladder dysfunction: Tumors in the lower spine or sacrum can affect nerves that control bowel and bladder function, leading to incontinence or retention 5.

Visual and Cranial Symptoms

• Vision problems: Skull base chordomas may cause double vision (diplopia), blurred vision, or even vision loss, depending on which cranial nerves are affected. Headaches are also common in these cases 3 5.

Systemic and Emotional Challenges

• Chronic fatigue: Many patients report ongoing exhaustion that is not relieved by rest 2.
• Emotional burden: Anxiety, depression, and confusion about the disease are frequently reported. Delayed diagnosis and the uncertainty of living with a rare cancer contribute to psychological distress 2.

Variability and Delayed Diagnosis

• The initial presentation can be non-specific, leading to delays in diagnosis—a major challenge for both patients and caregivers 2.
• Caregivers often experience their own burdens, including grief and difficulty managing the patient’s needs 2.

Types of Chordoma

Chordoma is not a single disease—there are distinct subtypes, each with unique features, prognoses, and treatment implications. Understanding these types aids in personalized care and research.

Type	Key Features	Typical Location(s)	Source(s)
Conventional	Most common; slow-growing, vacuolated cells	Sacrum, skull base, spine	6 7 13
Chondroid	Contains cartilaginous elements	Skull base (spheno-occipital)	1 6
Dedifferentiated	Aggressive, sarcomatous transformation	Any chordoma site	6 7
Poorly Differentiated	Pediatric/young adults, SMARCB1/INI1 loss	Skull base, cervical spine	8 9

Table 2: Chordoma Subtypes

Overview of Chordoma Subtypes

Chordomas are classified based on their cellular makeup and behavior.

Conventional Chordoma

• Most common subtype seen in adults, typically with slow but relentless growth 6 7 13.
• Histologically, it features large, vacuolated “physaliferous” cells in a gelatinous matrix 7 13.
• Usually occurs in the sacrococcygeal region, skull base, or spine 6 7.

Chondroid Chordoma

• Contains areas resembling cartilage (chondromatous differentiation) along with classic chordoma cells 1 6.
• Has a predilection for the spheno-occipital region of the skull base 1 6.
• Generally considered to have a slightly better prognosis than conventional type 6.

Dedifferentiated Chordoma

• Characterized by areas of high-grade sarcomatous (malignant) transformation within a conventional chordoma 6 7.
• Represents 2–8% of chordomas and is associated with a more aggressive course and poorer prognosis 6.
• Can develop at disease onset or emerge later as the tumor changes 6.

Poorly Differentiated Chordoma

• A recently described, aggressive variant, mostly affecting children and young adults 8 9.
• Shows loss of SMARCB1/INI1 expression, which is not seen in the other types 8 9.
• Presents as rapidly growing tumors, often in the skull base or cervical spine 8 9.
• Associated with worse overall survival and requires more aggressive, multimodal therapy 8.

Rarity and Challenges in Classification

• Chordomas are rare overall, with all subtypes together accounting for less than 5% of primary bone tumors 12.
• Some cases do not neatly fit into these categories, reflecting the complexity and diversity of the disease 7 9.

Causes of Chordoma

How does a tumor as rare as chordoma develop? The answer lies deep in embryonic development, but recent research has shed light on genetic and molecular contributors as well. While most cases are sporadic, some are linked to inherited factors.

Cause/Factor	Description/Details	Evidence/Marker	Source(s)
Notochordal Remnants	Originates from embryonic notochord tissue	Developmental/Anatomic	1 6 13 14
Brachyury Gene (TBXT)	Key notochord transcription factor; duplications linked to chordoma	Genetic biomarker/driver	11 14
SMARCB1/INI1 Loss	Seen in poorly differentiated chordomas, especially pediatric cases	Immunohistochemical marker	8 9
PI3K Pathway Mutations	Mutations in PI3K signaling in ~16% cases	Somatic mutation	11
LYST Mutation	Novel candidate gene found in 10% of cases	Somatic mutation	11
Familial Cases	Rare; hereditary duplications of Brachyury	Family history	14

Table 3: Causes and Risk Factors of Chordoma

Developmental Origins

• Embryonic notochord remnants: Chordomas arise from leftover cells of the notochord, a primitive structure that forms the core of the developing spine 1 6 13 14.
• These remnants may persist at the base of the skull, vertebrae, or tailbone, explaining the typical locations of chordomas 1 6 13.

Genetic and Molecular Factors

Brachyury (TBXT) Gene

• Brachyury is a transcription factor essential for notochord development 14.
• Duplications or overexpression of the TBXT gene are found in up to 27% of sporadic cases and are key drivers in familial chordoma 11 14.
• Brachyury serves as both a diagnostic marker and a potential therapeutic target 14.

SMARCB1/INI1 Loss

• Most commonly seen in poorly differentiated chordomas, particularly those in children and young adults 8 9.
• Identified by loss of SMARCB1/INI1 protein expression via immunohistochemistry 8 9.
• This molecular alteration confers a more aggressive clinical course and may guide therapy 8.

Other Genetic Changes

• PI3K pathway mutations: Present in roughly 16% of chordomas, these mutations are potentially targetable with new drugs 11.
• LYST gene mutations: Newly identified as recurrent in chordoma, though its role is still being studied 11.

Familial Chordoma

• Rarely, chordoma runs in families due to inherited duplications of the TBXT gene 14.
• Familial cases tend to present earlier and may involve multiple family members 14.

Environmental and Lifestyle Factors

• To date, no environmental, lifestyle, or preventable risk factors have been firmly linked to chordoma 14.

Treatment of Chordoma

Treating chordoma is challenging due to its resistance to conventional therapies and its tendency to recur. However, advances in surgical techniques, radiation modalities, and targeted therapies are improving patient outcomes. Treatment is typically tailored to the tumor’s location, size, subtype, and genetic profile.

Treatment	Approach/Details	Indications/Notes	Source(s)
Surgery	En-bloc excision with wide margins	Gold standard for localized disease	4 6 15 18 19
Radiation Therapy	Proton/carbon ion, IGRT	Adjuvant, salvage, or primary	4 6 15 16 18
Molecular Targeted	TKIs (imatinib, erlotinib, afatinib); Brachyury vaccine	Advanced/refractory cases	4 17
Chemotherapy	Limited effectiveness	Selected aggressive cases	4 8
Multimodal Therapy	Combination of surgery, RT, targeted	Poorly differentiated, recurrent	8 18

Table 4: Chordoma Treatment Options

Surgical Management

• Surgery is the cornerstone: En-bloc resection with wide margins offers the best chance for long-term control, especially for sacral and mobile spine chordomas 4 6 15 18 19.
• Complete resection is difficult due to the tumor’s proximity to vital structures; incomplete removal is associated with higher recurrence 15 18.
• In cases of recurrence, repeat surgery may be considered if feasible and safe 18 19.

Radiation Therapy

• Adjuvant radiation: Modern techniques such as proton beam, carbon ion, or image-guided radiotherapy (IGRT) are recommended, especially when surgical margins are close or incomplete 4 6 15 16 18.
• Primary radiation therapy: Used when surgery is not possible or as a supplement in recurrent disease 16 18.
• High-dose conformal radiation can improve local control rates, though chordomas are relatively radioresistant 16 18.
• Radiation toxicity: Preoperative planning with both the surgeon and radiation oncologist is crucial to minimize side effects and optimize outcomes 16.

Molecular Targeted Therapy

• Tyrosine kinase inhibitors (TKIs): Drugs such as imatinib, erlotinib, and afatinib have shown activity in chordomas with PDGFR or EGFR expression 4 17.
• Treatment selection is based on gene mutation screening and immunohistochemistry 17.
• Monotherapy with TKIs is preferred as first-line; combination therapy reserved for drug-resistant cases 17.
• Brachyury vaccine: An investigational immunotherapy targeting the brachyury protein, showing promise in early studies 17.

Chemotherapy

• Limited efficacy: Traditional chemotherapy is generally ineffective against chordoma, but may be considered in aggressive, dedifferentiated, or poorly differentiated subtypes, often as part of multimodal therapy 4 8.

Multimodal and Emerging Therapies

• Aggressive subtypes such as poorly differentiated chordoma require multimodal treatment (surgery, radiation, and sometimes chemotherapy) 8.
• Clinical trials: Ongoing research is evaluating newer targeted agents, immunotherapies, and combination approaches 4 17.

Recurrence and Long-Term Management

• High risk of local recurrence: Regular follow-up with imaging is essential 6 15 18.
• Salvage therapy: Repeat surgery and/or high-dose radiation may be used for relapsed cases, but prognosis is generally poorer after recurrence 6 18 19.
• Patient-centered care: Managing symptoms, rehabilitation, and supportive care are crucial for quality of life 2.

Conclusion

Chordoma is a rare but formidable cancer, presenting unique challenges at every stage—from diagnosis to treatment and survivorship. Advances in molecular understanding, surgical techniques, and targeted therapies are gradually improving outcomes, but much work remains to be done.

Key Points:

• Symptoms are highly variable and depend on tumor location, with pain, neurological symptoms, and functional impairment being most common.
• Types include conventional, chondroid, dedifferentiated, and poorly differentiated chordoma, each with unique characteristics and prognoses.
• Causes are rooted in embryonic notochord remnants, with genetic factors such as brachyury gene duplications and SMARCB1/INI1 loss playing a critical role.
• Treatment is multidisciplinary, relying on surgery, advanced radiation therapy, and, increasingly, molecular targeted therapies and immunotherapies.
• Recurrence is common, underscoring the need for ongoing research and patient-centered care.

By deepening our understanding of chordoma’s biology and clinical behavior, the medical community moves closer to more effective, personalized therapies and improved quality of life for those affected by this rare disease.