Clinical manifestations

Presentation and course

Approximately 50% of chordomas arise in the sacrum, 35% to 40% within the skull base and clivus, and 10% to 15% throughout the vertebral column (193; 74; 50; 65; 105; 126). In general, chordomas are relatively slow growing and often have a prolonged duration of symptoms before diagnosis. The specific symptoms and neurologic findings observed at presentation will vary according to the location of the tumor. Although these tumors often appear to be histologically benign, systemic metastases are seen in 10% to 40% of cases (193; 74; 65; 69; 150; 133). The most frequent sites for metastases are the lungs, regional lymph nodes, liver, bone, and skin.

Chordomas of the skull base, clivus, and intracranial cavity. Chordomas comprise 6.15% of all skull base tumors and 0.1% to 0.2% of all intracranial tumors (193; 74; 65). They occur most often in the clivus, but can arise in other areas such as the sphenoid sinus, cavernous sinus, occipital condyle, and sella (55; 193; 74; 219; 59; 211; 216; 149; 65; 03; 203; 56; 136; 215). Depending on the primary site of tumor involvement and direction of growth (eg, anterior, lateral, posterior), symptoms and signs may vary considerably. The mean age of patients with skull base chordomas is in the range of 38 to 45 years (211; 216; 03). In the majority of series, the most common symptoms are either diplopia or headache. Diplopia is the initial symptom in 50% to 90% of patients. The diplopia is usually horizontal and exacerbated by attempts at lateral gaze. Headache is noted at presentation in 25% to 60% of patients. In many patients, headache and diplopia develop simultaneously. Symptoms such as facial pain, vertigo, tinnitus, dysphagia, hoarseness, alterations of vision, and gait disturbance are present in 12% to 15% of patients (211; 216; 03).

On neurologic examination, the most common findings are cranial nerve palsies (168; 193; 59; 211; 216; 65; 03; 136). The fifth cranial nerve is involved most frequently, with abnormal function noted in 45% to 75% of patients. The deficit is usually unilateral but can be bilateral. Abducens palsy can be associated with dysfunction of cranial nerves II, III, IV, VI, and VII in 15% to 25% of patients. Although uncommon, isolated palsy of cranial nerves II, III, or IV is seen in some patients. Abnormalities of the lower cranial nerves (ie, IX, X, XI, XII) are noted in 25% to 40% of patients (59; 211; 216; 03). Similar to abducens palsy, the deficits are usually unilateral. Cranial nerves of the cerebellopontine angle (ie, VII, VIII) are rarely affected on examination at presentation but can develop in patients with large tumors. Pyramidal tract dysfunction is present in 15% to 20% of patients and develops from tumors that compress the ventral surface of the brainstem (193; 59; 65). The findings may be unilateral or bilateral and in some cases are associated with ataxia.

Chordomas of the sacrum. Chordomas represent the most common primary neoplasm of the sacrum (124; 193; 74; 17; 177; 12; 180; 63). They often reach substantial size prior to diagnosis because of the ample room for tumor growth before critical structures are disturbed. The median age at diagnosis is approximately 60 years; males are affected more often than females. The most common symptom (60% to 70% of patients) consists of persistent low back pain, which is slowly progressive and often present for 12 to 18 months before diagnosis. Patients occasionally complain of more specific locations of the pain, such as the coccygeal, buttock, or anal regions. The pain may have a radicular component to it, with radiation down the leg(s). This presentation often leads to the erroneous diagnosis of nonspecific "sciatica," delaying discovery of the tumor by many months. Rectal dysfunction consisting of alteration of bowel habits, tenesmus, or bleeding is common (approximately 40% of patients). As the tumor continues to enlarge, it usually grows ventrally and may encroach on the sacral foramina and nerve roots, causing neurologic dysfunction. Symptoms from sacral nerve root compression are variable and include perianal numbness, urinary hesitancy or retention, urinary incontinence, impotence, and rectal incontinence. General physical exam is typically intact, except for the rectal examination, which often demonstrates a presacral mass (193; 17). The neurologic examination may be normal or show evidence for sacral root dysfunction (eg, perianal numbness, loss of anal sphincter tone).

Chordomas of the mobile spine. Chordomas are uncommon tumors of the vertebral column (usually the vertebral body), representing less than 5% of all tumors in this region (50; 105; 217; 12; 180). Approximately 60% of vertebral chordomas arise in the lumbar region; 10% to 15% develop in the thoracic area, and 25% to 30% in the cervical spine. Rarely, chordomas can develop as extra-osseous, intradural spinal masses (11). Ventral tumor growth causes bone destruction and infiltration into paraspinal soft tissues, whereas dorsal expansion may cause nerve root displacement or spinal cord compression. The mean age of patients with spinal chordomas ranges from 45 to 50 years. Patients with these tumors often have a shorter duration of symptoms before diagnosis than patients with tumors of the sacrum, due to the smaller volume of bone in proximity to sensitive neural structures. In one series, the mean duration of symptoms prior to diagnosis was seven months (105). In the majority of cases (more than 90%), the initial symptom is localized pain in and around the involved vertebral body (217). There may be a radicular component to the pain from displacement or compression of nerve roots, with lancinating pain into a limb or anteriorly around the thorax. Other alterations of sensation such as dysesthesias or sensory deficits may occur. Cervical chordomas that grow ventrally and compress the esophagus may cause dysphagia (50). Occasionally, tumors can cause myelopathic weakness, gait ataxia, or sphincter dysfunction.

Prognosis and complications

Several authors have attempted to correlate pathological features of chordomas with prognosis (168; 59; 149). In a series of 48 mixed chordomas, Rich and colleagues were unable to detect a correlation between cellular pleomorphism, mitotic figures, or hyperchromatic nuclei with survival (168). The only histologic variable to correlate with survival was the presence of chondroid elements. Chondroid chordomas had a more indolent course, longer duration of symptoms, and increased survival. Tumors with greater than 10% necrosis were associated with shorter patient survival (149).

Patients less than 40 years of age appear to have improved survival and a better prognosis (59; 149). Although uncommon, when chordomas occur in children and adolescents, some reports suggest they may have a more indolent course and longer patient survival (78). Subcutaneous fat tumor extension is an independent predictor of decreased overall survival in sacral chordomas (230). Zou and colleagues evaluated clinical prognostic factors and surgical approaches in a series of 347 patients with clival chordoma and correlated the results with progression-free survival and overall survival (229). The 5- and 10-year progression-free survival rates for clival chroma were 59.2% and 47.9%, respectively. The 5- and 10-year overall survival rates were 77.3% and 63.9%, respectively. On multivariate analysis for progression-free survival and overall survival, gross total resection demonstrated significantly improved outcomes when compared with subtotal resection. A separate multivariate analysis demonstrated that older age, greater tumor size, and distant metastasis were correlated with decreased progression-free survival and overall survival. In contrast, surgical resection was correlated with increased progression-free survival and overall survival (114). A subsequent study has shown that a preoperative “FA score” (ratio of fibrinogen to albumin), serving as a biomarker of inflammation or malnutrition, may be an independent predictor of progression-free survival and overall survival (117). For clival chordomas, a nomogram that accounts for the degree of resection, E-cadherin, Ki-67, and VEGFA was shown to predict progression-free survival and may be of benefit for prognostication (227). Further, Ki-67 levels are higher in chordomas that invade the middle and lower clivus (97), suggesting that chordomas in the middle and lower clivus carry a worse prognosis.

The median overall survival for all types of chordoma, including all races and genders, is 6.29 years (132). The overall 5- and 10-year relative survival rates for all types of chordoma are 67.65% and 39.9%, respectively. Dedifferentiated chordomas, however, have a much shorter overall survival (20 months) when compared to conventional chordomas (142).

Complications of chordomas vary depending on the location and size of the tumor, as well as on the form of treatment. In general, patients with skull base tumors are most likely to develop cranial nerve palsies (usually VI, V, III, IX, X, VII), hemiparesis, and gait disturbance (181; 110; 65; 64). Less common complications include cerebrospinal fluid leak, hydrocephalus, hypopituitarism, hemorrhage, ataxia, and leptomeningeal spread with drop metastases (206). The most common complications of sacral chordomas are persistent pain (low back or radicular), urinary retention, and rectal incontinence (74; 17; 155). Less frequent complications include urinary incontinence, sexual dysfunction, lower extremity weakness, systemic metastases, with rare spread to the cerebrospinal fluid, cutaneous metastases, and pudendal neuralgia (95; 26; 67). In a review of 39 patients with chordomas of the sacrum and mobile spine, the incidence of systemic metastases was 28%, mostly to the lungs and soft tissues (15). A series of 37 patients with spinal chordomas had a 19% rate of metastasis, involving the lungs, liver and lungs, or remote spine (133). The most likely complications related to chordomas of the vertebrae are persistent back pain (localized, radicular, or both), dysesthesias, lower extremity weakness, and gait disturbance (194; 105). Less frequent complications include urinary retention or incontinence, dysphagia, fecal incontinence, and ataxia. Another recognized complication is seeding of chordoma cells along the surgical resection pathway (06). In their review of 82 patients, Arnautovic and al-Mefty noted an incidence of 7.3%, with a mean time to tumor growth of 12 months. Surgical seeding could occur from skull base and spinal chordomas.

Clinical vignette

Clivus chordoma. A 29-year-old male with an unremarkable past medical history presented with diplopia and headache. These symptoms were slowly progressive over several months and were eventually accompanied by complaints of difficulty with speech and gait. MRI scan revealed a large, enhancing, clival-based lesion with extension anteriorly into the sinuses.

On some of the higher cuts, posterior extension of tumor was causing compression of the brainstem. The neurologic examination demonstrated a partial left-sided third nerve palsy, right hemiparesis, and gait instability. The tumor was partially resected using a combined subfrontal-transethmoidal skull base approach. The pathology was consistent with chondroid chordoma; no sarcomatous features were evident. In the immediate postoperative period, the patient developed a stroke affecting the left side of the brainstem. He made an excellent recovery from the surgery and stroke during rehabilitation. Concomitantly, a 6-week course of external beam radiation therapy was administered. The patient was clinically stable on neurologic examination and follow-up MRI after several years.

Vertebral chordoma. A 51-year-old woman with an unremarkable past medical history presented with pain in the upper neck region that was slowly progressive over 4 to 6 months. These symptoms were initially attributed to arthritis and degenerative joint disease. In the last few months, the pain was accompanied by a fullness in the back of her throat and dysphagia. The dysphagia was mild at first but became more severe over several weeks. MRI scan demonstrated an enhancing 3 cm mass arising ventrally from the C3 vertebral body and extending into the posterior aspect of the tongue musculature.

Her neurologic examination was nonfocal, with intact cranial nerves and motor function. The patient was brought to the operating room for surgical resection of the lesion using a transoral approach and a temporary tracheostomy. An aggressive subtotal resection was performed in combination with C2 through C4 posterior fusion and halo placement. Pathology was consistent with a typical chordoma, without chondroid or sarcomatous features. Postoperatively, the patient received a 6-week course of external beam radiation therapy while undergoing in-patient rehabilitation. She remains neurologically intact and has noted significant improvement of the cervical spine pain and complete resolution of the dysphagia.

Biological basis

Etiology and pathogenesis

Chordoma cells derive from embryonic rests of the primitive notochord that persist within the axial skeleton (193; 74; 65). The notochord forms from ectodermal cells during the third or fourth week of development and is believed to act as an embryonic organizer (171). During the fourth to sixth weeks of development, mesenchymal cells from adjacent sclerotomes envelop the notochord as they merge to form the spinal vertebral bodies (171; 65). The notochord degenerates during this process, and by the seventh week it remains only between the vertebral bodies as the nucleus pulposus of the intervertebral discs. Pathologic studies of tissue using both light and electron microscopic techniques have demonstrated similarities between chordoma and human intervertebral disc (171; 65). It is postulated that incomplete degeneration of residual notochord may occur within the vertebral body at the junction of the adjacent sclerotomal regions. These incompletely degenerated rests can potentially undergo malignant transformation and develop into a chordoma.

Chordomas are generally slow-growing, unencapsulated neoplasms that are locally invasive within bone and soft tissues (168; 193; 74; 65; 176; 126). A pseudocapsule may be noted around tumors that grow into soft tissues or the dura mater. As the tumors enlarge, they often stretch cranial nerves and displace structures such as blood vessels and the brainstem. Grossly, the tumors are usually reddish or purple in color, with a nodular appearance to the surface. Internally, the mass is frequently gelatinous and soft; regions that contain cartilage or calcium are firmer. Foci of hemorrhage may be present and can be small or extensive. The size of the lesion can be variable, with sacral tumors often becoming extremely large. In one series of cranial base chordomas, average tumor volume was 58 cm3 (65).

On microscopic examination, chordomas can be grouped into several different histological categories, including a typical pattern, a chondroid pattern, and tumors with features of malignant degeneration (168; 193; 74; 31; 59; 149; 65; 176; 37; 126). The typical or classic pattern of chordoma (65% to 80% of all cases) is distinguished by a lobular arrangement, with the neoplastic cells disposed in solid sheets or irregular intersecting cords.

Many authors contend that the chondroid pattern (15% to 30% of all cases) is a separate histological variant of chordoma, although this is controversial (77; 168; 193; 74; 31; 59; 91; 149; 65; 176; 126). The chondroid pattern has been associated with a more favorable prognosis (77). By definition, chondroid chordomas contain regions of typical chordoma with physaliphorous cells, against a background of areas characterized by cartilaginous matrix that have stellate tumor cells occupying lacunar spaces (resembling chondrocytes) (77; 91). As in typical chordoma, anaplastic or aggressive features such as mitoses, necrosis, hypervascularity, and spindle cells are typically absent or rare (77; 168; 31; 59; 91; 149; 176).

A genetic linkage analysis of a cohort of patients with familial chordoma (103) suggests the presence of a locus for familial chordoma at chromosome 7q33 (103). A genetic linkage analysis on four multiplex families with familial chordomas was the first to reveal a new duplication in the region of 6q27, which contains the T (brachyury) gene (222). The T gene is important for notochordal development and is expressed in most sporadic chordomas. In fact, patients with a germline duplication of the T gene had a much earlier age of diagnosis (26.8 years) when compared to data from the general population (57 years). In addition, several patients with a germane duplication had multiple primary chordomas. These findings suggest that early screening of other at-risk family members with MR imaging of the neuraxis should be considered (157). A Lynch syndrome-associated chordoma was also reported (185). Germline alteration of DNA mismatch repair activity led to development of a chordoma with a high tumor mutational burden.

Data corroborate the importance of the brachyury gene in the pathogenesis of chordoma (192; 191), and it has become the histological standard of care for diagnosis. Presneau and colleagues analyzed the chordomas from 181 patients and noted frequent abnormalities and aberrations of the chromosome and gene (161). In 12 of 181 cases (7%) there was amplification of the T locus, with an additional two cases that showed focal amplification of the gene. Another 70 of 181 tumors (39%) were polysomic for chromosome 6, whereas 8 of 181 primary tumors (4.5%) showed a minor allelic gain of T on FISH analysis. When the T gene was knocked down in the chordoma cell line, U-CH1, which shows polysomy of chromosome 6q27, there was a marked decrease in cell proliferation. The same group then performed a functional genomics analysis of the brachyury gene in human chordoma samples, which demonstrates that the gene directly binds 99 other genes and indirectly influences the expression of another 64 genes (146). Brachyury appears to be in control of an oncogenic transcriptional network that involves signaling pathways that include components of the cell cycle and extracellular matrix. Another study suggests that one particular variant of brachyury is most prevalent in chordoma (159). The authors performed a single-nucleotide polymorphism analysis of the brachyury gene in a sample of 40 patients with chordoma. The common non-synonymous single nucleotide polymorphism rs2305089 was highly associated with risk of chordoma, with an odds ratio of 6.1. Overall, the extent of brachyury expression does not seem to correlate with prognosis in chordomas (191). However, inhibition of H3K23-demethylase in chordoma cells promotes epigenetic silencing of transcription factor brachyury and, thus, may represent a novel therapeutic target (36).

An immunohistochemical evaluation correlating expression of transforming growth factor alpha (TGFa), basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and several structural proteins correlated to chordoma recurrence was performed by Deniz and colleagues (48). The results suggest that high levels of expression of TGFa and bFGF are associated with higher rates of recurrence. In addition, higher TGF-alpha expression in skull base chordomas is associated with shorter progression-free survival when compared with a group with low TGF-alpha expression (228).

A series of six patients with advanced chordomas (sacrum 5, clivus 1) was evaluated for the expression of platelet-derived growth factor receptors (27). All six tumors demonstrated significant expression of platelet-derived growth factor receptors as determined by reverse-transcriptase PCR. Data from other researchers are in agreement and suggest that platelet-derived growth factor and platelet-derived growth factor receptors are frequently expressed in skull base chordomas, consistent with the presence of autocrine and paracrine loops (198; 154; 57). In a retrospective review of 187 primary skull base chordomas, elevated mean platelet volume and platelet distribution width were associated with poorer outcomes, suggesting that activated platelets may play a role in chordoma progression (118).

Studies by Naka and colleagues has analyzed the expression of tissue invasion-related enzymes in skull base chordoma and spinal chordoma (145; 143). They noted frequent expression of matrix metalloproteinase-1 and -2 (MMP-1 and MMP-2), tissue inhibitors of matrix metalloproteinases-1 and -2 (TIMP-1 and TIMP-2), cathepsin B (CatB), and urokinase plasminogen activator (uPA) in skull base tumors (144). In spinal chordoma, the expression of c-MET was correlated with the expression of CAM5.2 and stronger expression of MMP-1 and MMP-2 (143). Immunoreactivity for these proteins was significantly higher in tumors with aggressive infiltration into surrounding bone. In addition, higher expression of matrix metalloproteinase-1 and urokinase plasminogen activator was associated with a worse prognosis. Similar work by Chen and colleagues evaluated the expression levels of MMP-9 and VEGF in sacral chordomas (29). They noted higher expression of both MMP-9 and VEGF, and higher microvascular density, within tumor tissue in comparison to surrounding normal tissues. A significant correlation was noted between expression of MMP-9 and VEGF. Continuous disease-free survival time was significantly shorter in the MMP-9 positive group when compared to MMP-9 negative controls.

Similar studies have examined the role of the Akt/mTOR signaling pathway in chordomas (71; 160; 179; 49; 44). Activation of the Akt/mTOR pathways was demonstrated by all of the groups, with increased expression of phosphorylated Akt and mTOR and frequent loss of expression of the PTEN tumor suppressor gene. In the study by Han and colleagues, the mTOR inhibitor, rapamycin, was used against chordoma cell lines and was able to reduce mTOR activation and inhibit cellular proliferation (71). Schwab and colleagues used PI-103, an inhibitor of PI3K/Akt and mTOR activation, on chordoma cell lines and noted a reduction in activation of the Akt and mTOR pathways. In addition, PI-103 was able to inhibit proliferation and induce apoptosis in chordoma cell lines.

Using the technique of array comparative genomic hybridization, Hallor and colleagues evaluated a series of 21 chordomas for significant copy number changes (70). Their results showed a consistent loss of the CDKN2A and CDKN2B loci in 9p21, which were homo- or heterozygously lost in 70% of the tumors. These findings were subsequently corroborated by FISH analysis, suggesting that inactivation of CDKN2A and CDKN2B are involved in chordoma development. There is no significant difference in progression-free survival or overall survival based on CDKN2A expression alone (220). However, a multivariate cox model found that both homozygous 9p21 deletions and 1p3 deletions are independent prognostic factors in clival chordoma. The presence of both homozygous 9p21 deletions (> 25%) and 1p36 deletions (> 15%) portend the worse prognosis, whereas the presence of one of these deletions holds an intermediate prognosis, and the presence of neither offers the best prognosis. The authors suggest that this framework can offer insight into treatment planning after gross total resection. Namely, patients with a poor prognosis may require repeat surgery (if gross total resection is not obtained) or postoperative radiation, whereas patients with good prognosis and adequate first surgeries may enter observation (226).

CDK4 was found to be highly expressed in chordoma cell lines (122). Higher expression of CDK4 was correlated with the presence of metastasis and an increased risk of tumor recurrence. Subsequent work showed higher expression of CDK12 in chordoma cells (200). Inhibition of CDK12 significantly decreases cell proliferation and, thus, may serve as a novel therapeutic target. Similarly, higher expression of CDK9 correlates with recurrence and poorer outcomes in patients with chordoma, whereas CDK9 inhibitors decrease chordoma cell growth and proliferation (183).

Significant expression of survivin was noted in 70% of a cohort of 30 patients (28). Survivin expression was significantly higher in the group of tumors with recurrence in comparison to the group without recurrence and was inversely correlated with disease-free survival time. Survivin expression is an independent predictor of tumor progression (p=0.018) and mortality (p=0.008) (125). A similar study by Froehlich and colleagues evaluated the expression of survivin in a series of 50 chordomas, as well as three chordoma cell lines (60). Using the agent YM155 for survivin knockdown experiments, they noted decreased growth behavior in chordoma cells in a dose- and time-dependent manner. Use of YM155 led to G2/M arrest, decreased proliferation, an increase in polyploidy, and the induction of apoptosis.

Marucci and colleagues evaluated the MGMT promoter methylation status of nonrecurrent and recurrent clival chordomas (129). MGMT is a tumor treatment resistance enzyme that removes adducts to DNA that can occur during radiotherapy or chemotherapy. When the promoter is methylated, expression is reduced, making the cells more susceptible to treatment. In all of their tested nonrecurrent chordomas, the MGMT promoter was always unmethylated. In contrast, in a significant portion of the recurrent chordomas, the MGMT promoter was methylated. These results prompted the authors to speculate if recurrent clival chordomas might be responsive to temozolomide chemotherapy as adjuvant therapy. Efficacy of temozolomide in chordomas may be enhanced by concurrent use of PARP inhibitors, such as olaparib (25).

Epidemiology

Chordomas are rare neoplasms, representing only 0.1% to 0.2% of all intracranial tumors, 6.15% of all primitive skull base tumors, and 1% to 4% of primary malignant bone tumors (193; 74; 65; 132). The overall incidence rate in the United States is 0.088 chordomas per 100,000 persons (42). Chordomas can arise anywhere within the midline axial skeleton where the notochord existed (ie, clivus, sellar and parasellar region, nasopharynx, foramen magnum, vertebrae, and sacrococcygeal region) but have a predilection for the sacrum and clivus. In adults, approximately 50% of chordomas arise in the sacrum, 35% to 40% within the base of skull and clivus, and 10% to 15% throughout the true vertebrae (193; 74; 50; 65; 105). When chordomas affect the vertebral column, more than half will occur in the lumbar region, 25% to 30% in the cervical vertebrae, and 10% to 15% in the thoracic spine (50). In children, chordomas most often involve the skull base (219; 33). On rare occasions, chordomas can arise in extra-osseous or off-the-midline sites such as the transverse process of a vertebra, skin, paranasal sinuses, sella turcica, hypothalamus, or foramen magnum (55; 193; 74; 101; 34; 65; 11; 80).

Chordomas can occur at any age but are most common between the fourth and sixth decades of life, with a median age of 58.5 years (193; 74; 65; 132). Although these tumors can arise in children, less than 5% of all cases develop before 20 years of age (219; 33; 78). There is a male predominance in some series, especially for tumors of the sacrum, with a ratio ranging from 2:1 to 3:1 (193; 74; 65; 132). The overall male-to-female rate ratio for all chordomas is 1.54 (42). Although rare, chordomas can be familial (41; 103; 18; 214). The familial cases can often have an earlier onset than the typical patients with sporadic chordomas (214) and are more likely to occur at the skull base (157).

Differential diagnosis

Pathologically, several other tumor types must be considered, including ependymoma, schwannoma, neurofibroma, metastasis (eg, clear cell type), chondrosarcoma, and fibrous histiocytoma. Immunohistochemical analysis can be helpful in this differential diagnostic workup (171; 151; 37; 126). The immunohistochemical profile of typical chordomas illustrates the dual epithelial-mesenchymal nature of these tumors and consists of frequent positivity to cytokeratin, epithelial membrane antigen, and HBME-1, and less consistent staining for S100 protein and vimentin (135; 83; 171; 91; 65; 151; 126). Variable staining has also been noted with alpha1-antichymotrypsin, tissue polypeptide antigen, and tau proteins (24; 135; 84). Chondroid chordomas with a small cartilaginous component may have variable staining of S100, with preserved positivity to cytokeratin and epithelial membrane antigen (91). When the cartilaginous component is more robust (20% to 50%), the staining within the chondroid regions for cytokeratin and epithelial membrane antigen may become variable, with persistent positivity for S100 (91). Chondrosarcomas stain consistently negative for cytokeratin and epithelial membrane antigen because there is no epithelial component to these tumors. Chordomas with sarcomatous degeneration have an alteration of the immunohistochemical profile in the malignant regions containing spindle cells (82; 83; 204). The staining for vimentin becomes more prominent, whereas staining for cytokeratin and epithelial membrane antigen is markedly decreased. In some tumors, staining for S100 may also be reduced (204).

On CT and MRI, the differential diagnosis of a mass in the region of the clivus would include other tumors of the skull base such as chondrosarcoma, meningioma, metastases, pituitary adenoma, epidermoid, chondroma, plasmacytoma, craniopharyngioma, schwannoma, histiocytosis X, fibrous dysplasia, cholesterol granuloma, and paraganglioma (138; 108; 54; 203; 56; 126). In general, it is difficult to make a definitive diagnosis of clival chordoma based solely on CT or MRI characteristics (138). The differential diagnosis of tumors of the sacrum or vertebrae includes other destructive or sclerotic lesions such as metastases, Paget disease, plasmacytoma, chronic osteomyelitis, chondrosarcoma, and nerve sheath tumors (169; 43; 75; 139).

Diagnostic workup

Patients with a history and neurologic examination suspicious for a chordoma of the skull base, vertebral column, or sacrum require a radiologic evaluation with either computed tomography or magnetic resonance imaging (169; 111; 43; 153; 195; 138; 108; 115; 65; 87; 217; 56; 126; 22). CT and MRI are equivalent in their ability to delineate the presence of a tumor. Both modalities clearly demonstrate the mass within bone, bone erosion or destruction, and extension into soft tissues (169; 111; 43; 153; 195; 65; 37). Rarely, MRI may have trouble detecting small tumors confined within the margins of the clivus (195). On noncontrast CT, the tumor usually appears as a soft tissue mass, isodense or hyperdense with neural tissues, causing destruction of adjacent bone.

Bone windowed CT scans demonstrate the precise amount of bone destruction caused by the tumor, with sharp margins. Calcification is noted in 40% to 70% of chordomas (especially clival) with CT imaging. Small regions of sequestered bone can also be noted in approximately 15% to 20% of cases. MRI is inferior to CT in the ability to delineate the exact margins of bone destruction or the presence of calcification (111; 153). With the administration of contrast, chordomas always demonstrate contrast enhancement. The amount of enhancement may vary but is often dense and homogeneous.

In general, MRI with sagittal, coronal, and axial sections clearly define the margins of chordomas of the skull base, vertebral column, and sacrum (169; 111; 43; 153; 195; 138; 108; 115; 65; 87; 54; 75; 217; 224; 37; 56).

On T1-weighted images, 75% of tumors appear isointense, whereas 25% appear hypointense, compared to surrounding neural tissues (195; 65). With administration of gadolinium, chordomas usually enhance. As with CT, the degree of enhancement is variable; in most tumors, the pattern is heterogeneous. On T2-weighted images, chordomas are always hyperintense to all surrounding structures. The pattern of hyperintensity is homogeneous is 20% of cases and heterogeneous in the remaining 80% (mild in 30%, marked in 50%) (111; 195; 138). Tumor calcification, exact margins of eroded bone, and presence of sequestered bone are noted in some tumors, but these are not demonstrated as well as with CT. However, the multiplanar capability of MRI allows for better visualization of the extent of tumor margins and infiltration into soft tissues than is possible on CT. Sagittal MRI clearly shows the anterior-posterior margins of tumor involvement. For chordomas of the skull base, MRI is helpful for determining the anterior extension of tumor into the sinuses or nasopharynx and posterior extension towards the brainstem (111; 138).

The posterior fossa is affected by tumor (eg, brainstem compression, cranial nerve displacement) in approximately 80% of skull base tumors (138). Sagittal MRI is essential for tumors of the sacrum to determine the extent of the lesion anteriorly into the rectum and other soft tissues (169; 224). Coronal MRI images are useful for assessing lateral extension of skull base tumors towards the cavernous sinuses. The cavernous sinuses are infiltrated by tumor in approximately 65% of skull base chordomas (138). Furthermore, with sacral chordomas, coronal MRI can determine involvement of sacral nerve roots within the neural foramina. MRI is far superior to CT in demonstrating the relationship of tumor to cranial nerves and vascular structures (111; 153; 195; 138; 139; 56). Meyers and colleagues noted displacement of the carotid or basilar arteries in 57% of skull base chordomas (138). Furthermore, in 36% of their cohort, vascular encasement was present. Encasement of vessels by chordomas has also been reported by other authors (111; 153; 195; 217; 139). Universally, the lumen of encased vessels is not compromised by tumor, and they continue to have normal blood flow. MRI angiography can be very helpful to delineate tumor vasculature and the relationship of the mass to encased vessels (56). Most authors do not report any MRI signal characteristics that can be used to differentiate between typical chordomas and those with chondroid regions (138). However, Sze and colleagues noted that chondroid chordomas were less intense on T2-weighted images than were conventional chordomas (195). Assessment of mean quantitative T1 and T2 relaxation values (msec) has shown that chondroid tumors often have shorter times than conventional chordomas.

In addition to neuroimaging, patients with suspected chordomas of the clivus region should undergo pituitary function endocrine testing and neuro-ophthalmologic evaluation. For patients with suspected chordomas of the sacrococcygeal region, urodynamic testing and electromyography may be helpful.

Management

Treatment of chordomas can be limited by the invasive nature of these tumors, as they are often too infiltrative at diagnosis for a complete, curative resection (177; 65; 03). Even when the lesion is small and radical surgery is attempted, local recurrence rates remain high (ie, 50% to 100%). Therefore, the therapeutic approach for chordomas is primarily to maintain local control and minimize regional damage to neural structures. Despite the emphasis on local disease, systemic metastases can occur and are noted in 10% to 30% of patients (69; 150). The most common sites for metastases are the lungs, regional lymph nodes, liver, bone, and skin. Infrequent sites include cardiac muscle, brain, adrenal glands, pancreas, pituitary gland, and eyelids (69; 150). In the majority of patients, recurrence at the local site is most likely to affect morbidity and survival.

Surgical resection. Surgical resection is the first-line treatment of chordoma (193; 194; 74; 17; 59; 110; 65; 64; 03; 155; 15; 12; 156; 136; 215). The most aggressive resection possible should be attempted after initial diagnosis, depending on the location (eg, clivus, vertebral body, sacrum) and extent of the tumor. It appears that the degree of resection has a critical impact on local control rates and may correlate with overall survival. In a review of 51 patients with intracranial chordomas, Forsyth and colleagues found that the extent of resection affected survival (59). In a univariate analysis, the extent of resection was significantly associated with survival. For patients receiving only biopsy, the 5- and 10-year survival rates were 36% and 0%, respectively. In the cohort of patients undergoing subtotal resections, the 5- and 10-year survival rates were 55% and 45%, respectively. Recently developed nomograms predicting recurrence and survival in patients with chordoma strongly favor en bloc resection (137).

Chordomas of the skull base and clivus can be grouped according to their size and extension into contiguous areas (03). Type I tumors are small and restricted to one compartment of the skull base (eg, clivus or sphenoid sinus). Type II tumors are larger and extend to two or more contiguous areas of the skull base. Type III lesions are extensive and involve several contiguous compartments of the skull base (eg, clivus, sphenoid sinus, and middle fossa). Most series type I chordomas are rare and usually amenable to radical resection using a single skull base approach (65; 03). Type II tumors are most common (50% to 65%) and in many cases can also be radically resected using a single skull base procedure. The type III chordomas develop in 10% to 20% of patients and require two or more surgical procedures to attempt radical removal.

Numerous surgical approaches and techniques are available for resection of skull base and clivus chordomas (07; 38; 181; 110; 65; 64; 68; 128; 134; 03; 94; 173). The approach will depend on the location of the tumor and the degree of extension from the primary site. Most often, tumors are centered within the lower, middle, or upper clivus and extend into the cavernous sinus or petrous apex. The four most common approaches allow for an extensive resection of tumor either extradurally or intradurally. The subtemporal, transcavernous, transpetrous apex approach is used most often (30% to 35%) and provides access to the clivus, cavernous sinus, sella turcica, and petrous apex (65; 134; 03). The extended frontal approach is used in 25% to 30% of patients and is advantageous for tumors with extension into the orbits, ethmoid sinus, and anterior skull base (110). The subtemporal-infratemporal approach is utilized in approximately 20% of patients and offers excellent exposure of the middle fossa, clivus, and lateral skull base. For chordomas of the lower clivus, temporal bone, and occiput, the extreme lateral transcondylar and transjugular approach is used (approximately 15% of patients). Transoral, transmaxillary, transcervical-transclival, anterior cervical, and transsphenoidal procedures have traditionally been less common (07; 38; 181; 65; 64; 68; 128; 134; 94; 203). However, a German retrospective review of 50 patients with clivus chordomas reported the use of a transsphenoidal approach in 51.7% of primary cases, a much higher rate than previously reported (231).

Studies using the most advanced skull base approaches for removal of chordomas report various results. Radical or total resection of tumor is achieved in 43.5% to 55% of patients, near total or subtotal resection is noted in 40% to 47% of patients, and partial resection is attained in 8% to 10% of patients (110; 65; 64; 03; 173; 215). In a series reported by Samii and colleagues, the transethmoidal approach was used most often (36.3%), with gross total removal of tumor in 49.4% and subtotal removal in 50.6% of cases (173). The 5- and 10-year survival rates were 65% and 39%, respectively. Using a historically controlled study design, Di Maio and colleagues reviewed their experience in surgical resection for cranial base chordomas, comparing results using older techniques from 1988 to 1999 to the results from 2000 to 2011 using more advanced skull base approaches (52). The mean 5-year overall survival and recurrence-free survival for the entire cohort (N = 95) was 74% and 56%, respectively. Complete resection rates were similar in a study that compared advanced skull base approaches with a historical control of traditional surgical approaches (74% vs. 68%) (52). However, the modern approach had reduced complication rates overall. Although there was no difference in the 5-year recurrence-free survival rate, there was a higher overall survival rate in the more modern cohort (93% vs. 64%, p = 0.012).

Some surgeons are now attempting more "minimally invasive" approaches, using endoscopic techniques for removal of clival chordomas (45; 170). In the series of 12 patients reported by Dehdashti and colleagues, endoscopy was used during an expanded endonasal approach, with gross total removal of tumor in seven patients (58%) and subtotal removal (more than 80%) in another five patients (42%). No tumor recurrence was noted with a median follow-up of 16 months. The technique was well tolerated. Endonasal approaches may minimize the incidence of postoperative cranial nerve palsies when compared to other approaches (152). Similar results have been reported in a series of patients with clival chordomas in a study by Saito and colleagues (170). Another "minimally invasive" approach is the expanded transsphenoidal approach, which has been used in combination with neuro-navigation by Al-Mefty and co-workers in a series of 38 clivus chordomas (04). With this technique, gross-total resection was achieved in 79% of the cases.

Sacral chordomas are often extremely large at diagnosis; however, most experts advise radical resection whenever possible (193; 74; 17; 174; 155; 213; 224; 225; 15; 180; 63). Similar to the experience with skull base tumors, recurrence-free survival is improved after radical or near total resection. For tumors of the lower sacrum and coccygeal region, many authors recommend a posterior approach (74; 155; 213), whereas others prefer a combined anterior-posterior approach (17). Tumors of the upper sacrum are resected most efficiently with a staged, combined anterior-posterior approach (193; 74; 17; 174; 155). Computer navigation–aided technology may improve the accuracy of resection of chordomas of the upper sacrum (223). Transcatheter arterial embolization of the main arteries feeding the tumor, prior to attempts at radical resection, has also been utilized as preoperative embolization can lead to less intraoperative blood loss, a better view of the surgical field, and facilitation of maximal removal of the sacral chordoma (221). Regardless of the approach used to resect the tumor, it is important to attempt preservation of the upper sacral nerve roots and the pudendal nerve. If the bilateral S2 nerve roots are sectioned during surgery, urogenital and rectal function will be lost or impaired. If both S nerve roots are preserved, 50% of patients will retain at least partial bladder and bowel control (174; 155). To maintain normal bowel continence, preservation of at least one set of ipsilateral S1, S2, and S3 nerve roots is recommended. The local recurrence rates are approximately 25% to 30% for tumors removed en bloc by radical resection (193; 74; 17; 225). If the tumor is removed by subtotal or partial resection, local recurrence rates increase to approximately 60% to 65%.

It is also recommended that chordomas of the true vertebrae be radically resected whenever feasible (194; 74; 50; 75; 15; 20; 180; 32). For tumors of the cervical vertebrae, an anterior approach to perform a corporectomy, followed by bone grafting, is commonly utilized (50; 13). For carefully selected patients, a 2-stage, en bloc resection of the tumor may also be considered (162; 32). Although an en bloc resection of cervical tumors is the preferred approach, it often is not achievable (13). Thoracic tumors are best approached by thoracotomy or a staged procedure that combines a laminectomy and thoracotomy (74). Lumbar chordomas will usually require an anterior approach, but on occasion, a posterolateral approach may be necessary (74; 75; 20).

Radiation therapy. Although radical resection is considered in each patient with a chordoma of the skull base, vertebrae, or sacrum, it is often impossible due to the invasive nature of these tumors. Therefore, radiation therapy to eradicate residual or recurrent disease is an important therapeutic consideration in many patients (193; 74; 59; 177; 65; 225; 12; 136). Unfortunately, chordomas have proved to be relatively radioresistant at traditional doses. The clinical results in most radiation therapy trials of chordomas have demonstrated only modest improvements in local control, recurrence-free survival, and overall survival (16; 09; 10; 102; 08; 196; 201). Role of radiotherapy after gross total resection remains unclear (66).

Early reports in the radiation oncology literature using photon-based megavoltage therapy suggested a dose-response relationship for chordoma (196; 201). It was recommended that patients receive at least 6000 to 7000 cGy to the tumor bed for optimal response. However, other studies have been unable to document a consistent dose-response relationship for chordoma using conventional photon techniques (175; 40; 65; 196). Forsyth and colleagues evaluated the results of 51 patients with intracranial chordomas and determined that conventional irradiation did not affect the overall survival of the cohort, but did prolong the disease-free survival, especially in younger patients (59). The 5- and 10-year disease-free survival in irradiated patients was 39% and 31%, respectively. A similar improvement of progression-free survival, without a change in overall survival, has been reported by Thieblemont and colleagues in 26 patients with chordomas of various sites (201). A single-center retrospective review showed that higher intensity stereotactic radiosurgery (24 Gy) for sacral and spinal chordomas had improved local recurrence-free survival but had a similar overall survival to lower dose stereotactic radiosurgery (96). A retrospective review of the National Cancer Database revealed an improvement in overall survival for patients with positive surgical margins after undergoing adjuvant radiotherapy but no improvement in overall survival for patients with negative surgical margins after undergoing adjuvant radiotherapy (51). Multivariate analysis revealed that high-dose radiotherapy (> 65 Gy) further improved overall survival when compared to external beam radiation therapy. Additional studies have shown no improvement in sacral tumor outcome after low-dose radiotherapy but, instead, only an association with wound complications and sacral stress fractures (81). As such, the use and dose of radiotherapy after surgery for chordomas should be considered on an individualized basis.

Irradiation of chordomas with charged particles (ie, protons, helium, neon, carbon) has shown promise as a more efficacious therapeutic option (16; 09; 10; 177; 65; 196; 85; 199; 148; 178; 89; 136; 147; 90). There are several radiobiological advantages of charged particles over photons. The high linear energy transfer of charged particles allows for a more defined and superior dose distribution (ie, steeper fall-off in dose). Higher doses can be prescribed to the tumor volume with minimal risk of augmented toxicity to surrounding normal structures.

Austin-Seymour and colleagues have used fractionated proton irradiation for skull base chordomas and chondrosarcomas, administering a mean total dose of 69 GyE (09; 10; 196). The 5- and 10-year local control rates were 82% and 58%, respectively, whereas the 5- and 10-year disease-free survival rates were 76% and 53%, respectively. The median time to local failure was 53 months. In their opinion, these results represent a significant improvement over the results of conventional radiation techniques. Similar results have been reported by Hug and colleagues in a review of 33 patients with skull base chordomas (85). Using a mean target dose of 70.7 Cobalt Equivalent, they achieved a local control rate of 76% and an actuarial 5-year survival rate of 79%.

A meta-analysis of the literature has reviewed 210 articles and analyzed a total of 416 patients who had received proton therapy for skull base chordoma (05). These data were tabulated and then compared to the results from other irradiation techniques. Although no randomized phase III studies were available, the remaining studies did suggest that the use of protons allows for the use of higher doses (up to and above 70 CGE) and more precise tumor targeting. Local control rates at 3 and 5 years were in the range of 67.4% to 87.5% and 46% to 74%, respectively. The estimated overall survival rates at five years were 66.7% and 80.5%, and at 10 years were 54%. These results were superior to those obtained with conventional irradiation approaches, with acceptable toxicity. Thus, use of proton beam radiotherapy has become the standard approach at many specialized cancer centers. A cohort of 13 patients using postoperative proton therapy with a simultaneous integrated boost to the gross tumor volume had an excellent response, with 100% local control and overall survival at 10.7 months’ median follow-up (158). A meta-analysis of proton beam radiotherapy for postsurgical treatment of skull base chordomas provided level IIb/III evidence that proton beam therapy demonstrated improved long-term local control and survival in comparison to other radiotherapy modalities (131). In addition, chordoma cell lines have been shown to be killed at higher numbers by brachyury-specific T cells after proton beam therapy (62). Proton therapy is being used in brachyury-specific vaccine trials. Further, the combination of photon and tomotherapy seems to improve organ at risk sparing and the incidence of late toxicities (14).

Results from studies with carbon ion radiotherapy have been reported by several groups and are similar to those with protons. In a series of 24 patients with skull base chordomas treated with carbon ions, the 2-year local tumor control rate was 90% (178). In a similar study of 32 patients with skull base chordomas, carbon ion radiotherapy was utilized after aggressive resection (197). The 3-year recurrence-free survival rate was 70%, as opposed to 57.1% for patients receiving more conventional radiotherapy (p= 0.001). For patients with unresectable sacral chordomas, carbon ion radiotherapy has also been effective (89; 90; 88). Most patients received a dose of 67.2 to 70.4 Gray equivalents in 16 fractions, with 5-year local control, overall survival, and disease-free survival rates of 77.2%, 81.1%, and 50.3%, respectively (88). A nationwide multicenter study in Japan of patients with unresectable sacral chordoma showed 5-year overall survival, progression-free survival, and local control rates of 84%, 48%, and 72%, respectively, after patients underwent carbon ion radiotherapy (47). A large study from a German group used a Raster scan technique to evaluate 155 patients with skull base chordoma after surgery and irradiation with carbon ions from 1998 to 2008 (207). The median total dose was 60 gray, with a median boost planning target volume of 70 mL. The 3-year, 5-year, and 10-year local control rates were 82%, 72%, and 54%, respectively. The 3-year, 5-year, and 10-year overall survival rates were 95%, 85%, and 75%, respectively. No late toxicity from carbon ion therapy was noted in the cohort. Another report from the same German group applied carbon ion beam therapy to a series of 56 patients with sacral chordomas, either alone or in combination with photon IMRT (208). The median total dose was 66 Gy (range 60 to 74 Gy). The 2- and 3-year local control rates (median follow-up time of 25 months) were 76% and 53%, respectively, with an overall survival rate of 100%. However, follow-up analysis in 2020 revealed that the 5-year rates for local control, progression-free survival, metastasis-free survival, and overall survival were 53%, 53%, 52%, and 74%, respectively, suggesting that dose escalation may need to be considered (21). A prospective study using a customized dual particle strategy employing both proton and carbon ion therapy for the treatment of skull base chordoma displayed efficacy and safety, while also suggesting that gross total tumor volume, tumor location, and dose coverage are independent prognostic factors for local control (86).

Other methods of irradiation of chordoma include brachytherapy with radioactive seeds (eg, iodine-125), radiosurgery, intensity-modulated radiotherapy, conformal techniques, intraoperative radiotherapy for sacral tumors, and radiation sensitizers (109; 09; 106; 65; 141; 107; 202; 93; 163; 99). It is difficult to evaluate the efficacy of these modalities because of the small number of patients that have been treated and the limited follow-up intervals reported (09; 65).

In a small cohort of nine patients with sacral chroma treated with argon-helium cryoablation, all patients were alive at the time of follow-up (median follow-up 33 months), and two had experienced local recurrence (116). Another small cohort (n=4) showed 90% recurrence at five years after cryoablation of sacrococcygeal chordoma, suggesting that cryoablation alone is unlikely curative (30).

A review of experience using Gamma Knife radiosurgery after tumor resection of skull base chordomas suggests efficacy in patients with low residual tumor volumes (72). With marginal doses of at least 15 Gy, the actuarial 5- and 10-year survival rates were 80% and 53%, respectively. The 5- and 10-year actuarial local tumor control rates were 76% and 67%, respectively. The local control rates were significantly improved when residual tumor volume was 20 mL or less (p = 0.018). Another review of Gamma Knife treatment of residual skull base chordomas noted survival of 90.9% and 75.8% after 3 and 5 years, respectively (121). The actuarial tumor control rate was 64.2% and 21.4% after 3 and 5 years, respectively. An update demonstrates a similar experience using Gamma Knife in the setting of recurrent disease in the clivus after an initial aggressive resection (92). A report by the North American Gamma Knife Consortium analyzed data from six centers, for a total of 71 patients with skull base chordomas who had undergone treatment (100). The median patient age was 45 years, with a median dose of 15.0 Gy (range, 9 to 25 Gy) and median target volume of 7.1 cm3 (range, 0.9 to 109 cm3). After a median follow-up of five years, there were 23 patient deaths. The 5-year actuarial overall survival was 80%: 93% for the cohort that had not received prior irradiation (N = 50) and 43% for the cohort that had received prior radiotherapy. The overall 5-year treated tumor control rate was 66%.

Chemotherapy. Historically, the regimens used to treat chordomas have been designed to resemble protocols used for soft-tissue sarcomas. Unfortunately, few patients have responded to this approach. Chemotherapeutic agents that have been used (as single agents or in combination) without success include methotrexate, vincristine, cisplatin, doxorubicin, etoposide, actinomycin D, and cyclophosphamide (194; 74; 58; 201). A study showed that cytarabine reduces the viability of human chordoma cells in vitro, but further investigation in animal studies is required (205).

Fleming and colleagues report two patients with malignant sacral chordomas and lung metastases in whom chemotherapy produced objective responses (58). One patient responded to a multiagent regimen consisting of etoposide, cisplatin, vincristine, dacarbazine, cyclophosphamide, and doxorubicin administered intravenously over 3 days every 4 to 5 weeks. The second patient responded to this multiagent regimen for five cycles and then progressed. A second regimen of single-agent continuous infusion ifosfamide was initiated, which produced dramatic shrinkage of the lung lesion.

A series of six tumors expressing platelet-derived growth factor receptors were treated with imatinib, a TK inhibitor of platelet-derived growth factor receptor. Overall, the cohort responded with stabilization of disease, several of which were long-term. In addition, four of five symptomatic patients had improvement of symptoms (27; 53). A follow-up study included 56 patients with advanced chordoma using imatinib in a phase II clinical trial (187). There was only one objective response (partial response, overall response rate of 2%), whereas 70% of the cohort demonstrated stable disease. There were also minor responses (< 20% tumor reduction) noted in nine patients. The median progression-free survival for the entire cohort was nine months. Follow-up phase II studies from Stacchiotti showed that imatinib did have some antitumor activity in chordoma but failed to meet its primary endpoint, displaying no statistically significant overall response rate (189). Higher powered studies are needed to further assess the use to imatinib in chordoma. Regorafenib, a promiscuous RTC inhibitor targeting angiogenesis, proliferation, and metastasis pathway, was found to be ineffective (113).

In a series of 10 patients with progressive chordoma, imatinib (400 mg/day) was combined with rapamycin (sirolimus 2 mg/day), an mTOR inhibitor (188). Responses and stabilization of disease were durable for more than six months in 89% of the cohort. In a related paper, cell lines from a recurrent clival chordoma were used to establish tumor xenografts in severe combined immunodeficiency (SCID) mice (167). Molecular analysis revealed persistent expression of brachyury, activation of the mTOR pathway, and mutation of the K-RAS gene. Treatment of the cell lines and xenografted tumors with rapamycin resulted in significant growth inhibition. When rapamycin was then used for the patient with the recurrent clival chordoma, there was a 6-fold reduction of tumor growth that was durable for 10 months.

A patient has been reported with a sacral chordoma that was shown to express epidermal growth factor receptor, in whom a molecular chemotherapy approach was also successful (79). The patient had local progression and enlargement of pulmonary metastases, prompting placement on a combination of cetuximab and gefitinib. The sacral tumor and pulmonary metastases responded with partial responses that have been maintained for greater than nine months.

An Italian phase 2 study used lapatinib, a tyrosine kinase inhibitor that blocks HER2/neu and EGFR, in a series of 18 EGFR-positive progressive chordomas (190). There were six partial response (33%) and seven stable disease (38.9%) patients, with a median progression-free survival of eight months using response evaluation criteria in solid tumor (RECIST) criteria. A similar patient with a spinal chordoma was on a clinical trial of erlotinib and linsitinib (IGF-1R/insulin receptor inhibitor) and had a partial response after 18 months of treatment (02). The patient was able to maintain the tumor shrinkage for another 43 months--thereby achieving a durable response for five years. Afatinib is another EGFR inhibitor that was tested against a panel of chordoma cell lines by Magnachi and colleagues (127). It was the only anti-EGFR drug to have inhibitory activity against every cell line in the panel. When the molecular mechanisms were analyzed in more detail, the antiproliferative IC50s correlated with the ability of the drug to promote degradation of EGFR and Brachyury. In addition, high EGFR phosphorylation correlated with higher sensitivity to afatinib. A phase 2 clinical trial of afatinib in patients with advanced chordoma is currently ongoing (127).

Using chordoma cell lines with overactivity of the cell cycle (via loss of CDKN2A and p16, and activation of the CDK4/6 and Rb pathways), treatment with palbociclib was able to significantly inhibit tumor cell growth in vitro (212; 122). Larger scale studies and clinical trials are needed to assess safety and efficacy.

The vascular endothelial growth factor (VEGF) pathway is also being explored as an avenue of treatment. Lipplaa and co-workers treated five patients with unresectable or metastatic chordoma with sunitinib and pazobanib--VEGF receptor inhibitors (119). Two of four patients on pazopanib had stable disease for 14 and 15 months, respectively, whereas the patient treated with sunitinib had a partial response that lasted for 27 months. Ribeiro and colleagues reported the case of a patient with a multifocal recurrence of a lumbar spine chordoma that had further progression after re-resection and a course of radiotherapy (166). He was then placed on pazopanib (800 mg/day), and had an objective response, with a 23.1% reduction in size of the recurrent lesions, which was durable. A single-arm, phase II study of 30 patients with advanced chordoma showed a median progression-free survival of 18 months and tolerable grade 3 side effects (hypertension, proteinuria) after treatment with apatinib, a tyrosine kinase inhibitor that selectively binds to VEGFR2 (120).

The immune checkpoint pathways and associated immune checkpoint inhibitor drugs (eg, ipilimumab, nivolumab, pembrolizumab) are becoming very important for systemic therapy of many solid tumors (23; 01). Work by Mathios and colleagues has shown that chordomas express PD-1, and that expression of PD-1 is further induced by proinflammatory cytokines in the tumor environment (130). Ambient expression of PD-L1 is not very high in chordoma tissue but is present on tumor-infiltrating macrophages and lymphocytes. Based on this early data, Fujii and colleagues used the anti-PD-L1 IgG1 monoclonal antibody, avelumab, on a series of chordoma cell lines (61). Avelumab is capable of inducing antibody-dependent cell-mediated cytotoxicity (ADCC) and was able to induce ADCC of chordoma cells when incubated with brachyury-specific CD8+T cells. Pembrolizumab was investigated in 34 subjects with chordomas. Partial response was observed in 12% with an eight months of mean duration of response (19). Stable disease was observed in 74% with 18% progressing. Cytotoxic T lymphocyte antigen-4 (CTLA-4) expression in chordoma tumor cells and tumor infiltrating lymphocytes could provide yet another therapeutic target for patients with chordoma (73). Combination of durvalumab, an anti-PDL1 antibody, combined with tremelimumab, an anti-CTLA-4 antibody, showed activity (186).

One patient with metastatic chordoma and the A1209fs mutation of the PBRM1 gene had a progression-free survival of 9.3 months after receiving pembrolizumab as a second-line therapy (218). Another patient with sacral chordoma showed a partial response to erlotinib after being refractory to imatinib (209). Larger scale trials are needed to further assess the efficacy of immunotherapy in chordoma.

Anti-Brachyury therapy. Given that brachyury is expressed on nearly 100% of chordomas, use of therapy targeting brachyury alone or in combination with other treatments are being investigated (182; 184). A phase 1 study displayed both safety and immunogenicity of a yeast-based vaccine targeting brachyury in patients with both carcinomas and chordomas (76). However, a phase II trial using the same vaccine combined with standard radiotherapy was terminated after an interim analysis revealed no difference in the overall response rate between placebo and treatment groups. Median progression-free survival in the vaccine group (20.6 months) and the placebo group (25.9 months) were similar, though this study was not powered to assess progression-free survival (46). Other phase II trials studying use of a viral vector-based vaccine expressing brachyury are still undergoing (NCT035952298).

Chordoma is a complex disease requiring input of many subspecialists. Patients are best served at institutions with multidisciplinary experts familiar with this disease (98).

Special considerations

Pregnancy

The only risk associated with chordomas and pregnancy would be radiation to the sacral region in a pregnant patient or the possible loss of fertility related to surgery or radiation or both for tumors in the region of the pituitary. Pregnancy does not affect the clinical behavior of chordomas of the clivus, sacrum, or true vertebrae.

Anesthesia

If the transoral or transmaxillary surgical approaches are used, the airway needs to be protected, and a tracheostomy may be necessary. In patients with skull base chordomas large enough to elevate intracranial pressure, agents that produce excessive sedation and ventilatory depression should be avoided because these could exacerbate intracranial pressure (112; 39). Hypotonic fluids should also be avoided whenever possible. During the induction and maintenance of anesthesia, agents that minimize hypertension, cerebral vasodilation and blood flow, cerebral metabolic rate, chest wall rigidity, and hypercapnia should be chosen.